U.S. patent number 10,765,693 [Application Number 16/583,570] was granted by the patent office on 2020-09-08 for polymorphic compounds and uses thereof.
This patent grant is currently assigned to Astrocyte Pharmaceuticals, Inc.. The grantee listed for this patent is Astrocyte Pharmaceuticals, Inc.. Invention is credited to Lisa Michelle Grove, David T. Jonaitis, Russell Birch Poe.
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United States Patent |
10,765,693 |
Poe , et al. |
September 8, 2020 |
Polymorphic compounds and uses thereof
Abstract
The present invention provides compounds and methods of use
thereof for treatment of certain disorders and conditions, for
example brain injuries such as stroke or traumatic brain
injuries.
Inventors: |
Poe; Russell Birch (Groton Long
Point, CT), Jonaitis; David T. (Brookston, IN), Grove;
Lisa Michelle (Lafayette, IN) |
Applicant: |
Name |
City |
State |
Country |
Type |
Astrocyte Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Assignee: |
Astrocyte Pharmaceuticals, Inc.
(Cambridge, MA)
|
Family
ID: |
1000005039974 |
Appl.
No.: |
16/583,570 |
Filed: |
September 26, 2019 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20200093848 A1 |
Mar 26, 2020 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62736979 |
Sep 26, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/7076 (20130101); C07H 19/16 (20130101); C07B
2200/13 (20130101) |
Current International
Class: |
A61K
31/7076 (20060101); C07H 19/16 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1624753 |
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Jan 2012 |
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EP |
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WO-2006031505 |
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Mar 2006 |
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WO |
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WO-2006091905 |
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Aug 2006 |
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WO |
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WO-2007020018 |
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Feb 2007 |
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WO |
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WO-2008021552 |
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Feb 2008 |
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WO |
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WO-2010014921 |
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Feb 2010 |
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WO |
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WO-2011077435 |
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Jun 2011 |
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WO |
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WO-2014160502 |
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Oct 2014 |
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WO |
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WO-2016123672 |
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Aug 2016 |
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WO |
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WO-2017/185061 |
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Oct 2017 |
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WO |
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WO-2019157317 |
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Aug 2019 |
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WO |
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Primary Examiner: Lau; Jonathan S
Attorney, Agent or Firm: Reid; Andrea L. C. Arico; Joseph W.
Dechert LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Patent
Application No. 62/736,979, filed on Sep. 26, 2018; the entirety of
which is hereby incorporated by reference.
Claims
We claim:
1. A solid form of Compound A: ##STR00015## wherein said solid form
has one or more peaks in its XRPD selected from those at about 8.0
and about 13.1 degrees 2-theta.
2. The solid form according to claim 1, wherein said solid form is
a crystalline solid substantially free of amorphous Compound A.
3. The solid form according to claim 1, wherein said solid form is
substantially free of impurities.
4. The solid form according to claim 1, having two peaks in its
XRPD selected from those at about 8.0 and about 13.1 degrees
2-theta.
5. The solid form according to claim 1, having an XRPD
substantially similar to that depicted in FIG. 1.
6. A pharmaceutical composition comprising the solid form of claim
1 and a pharmaceutically acceptable carrier, excipient, or
adjuvant.
7. A solid form of Compound A: ##STR00016## wherein said solid form
has one or more peaks in its XRPD selected from those at about 9.5,
about 10.5, and about 13.8 degrees 2-theta.
8. The solid form according to claim 7, having at least two peaks
in its XRPD selected from those at about 9.5, about 10.5, and about
13.8 degrees 2-theta.
9. The solid form according to claim 7, having an XRPD
substantially similar to that depicted in FIG. 10.
10. The solid form according to claim 7, wherein said solid form is
a crystalline solid substantially free of amorphous Compound A.
11. The solid form according to claim 7, wherein said solid form is
substantially free of impurities.
12. The solid form according to claim 7, having peaks in its XRPD
at about 9.5, about 10.5, and about 13.8 degrees 2-theta.
13. A pharmaceutical composition comprising the solid form of claim
7 and a pharmaceutically acceptable carrier, excipient, or
adjuvant.
Description
FIELD OF THE INVENTION
The present invention relates to compounds and methods of use
thereof for treating, ameliorating, or promoting recovery from
certain conditions of the brain, central nervous system (CNS), or
cardiovascular system such as a brain injury, a neurodegenerative
condition, or cardiac ischemia.
BACKGROUND OF THE INVENTION
Brain injuries are a distressingly common medical condition and one
of the leading causes of morbidity and mortality worldwide. The
brain is particularly susceptible to injury as neurons have a
limited capacity to repair. When an individual is born, the brain
already has essentially all the neurons it will have in life.
Unlike other cells in the body, neurons stop reproducing shortly
after birth. If these cells are injured or die, they are not
replaced, often culminating in the disabling and largely
irreversible degradation of a person's cognitive and sensorimotor
capacity. Conditions that result in nerve cell death and damage
range from ischemic episodes (e.g., stroke) and trauma, to
degenerative disorders (e.g., Alzheimer's disease).
Injury to the Central Nervous System (CNS) is a substantial cause
of death and disability worldwide. For example, according to the
CDC approximately 1.7 million people sustain a Traumatic Brain
Injury (TBI) annually, costing the U.S. economy in excess of $60
billion per year in terms of medical costs and lost productivity
(Finkelstein, E; Corso, P; Miller, T, The Incidence and Economic
Burden of Injuries in the United States, Oxford University Press:
New York, 2006). Additionally, stroke is the third leading cause of
death in the U.S. with an estimated incidence of 795,000 cases
annually, a major cause of disability, and costing the U.S. economy
over $34 billion per year (NINDS, 2014; stroke.nih.gov; and
Mozaffarian D, Benjamin E J, Go A S, et al. "Heart disease and
stroke statistics-2015 update: a report from the American Heart
Association," Circulation. 2015; e29-322).
In the acute setting, there is an opportunity to treat patients
within 24 hours that can limit the extent of the damage.
Immediately after an ischemic or hemorrhagic stroke, the site of
insult in the brain typically contains a core of tissue that is
irreversibly damaged, and then also an area of viable but at-risk
tissue called the penumbra. During this period, the insufficient
oxygen and glucose supply to brain cells results in further
secondary injury to the penumbra. The lack of oxygen and glucose
decreases energy production by cell mitochondria. An immediate
effect of this energy depletion is failure of the ion pumps, which
by elevating extracellular potassium (K.sup.+) ions, results in
waves of recurrent spreading depolarizations in brain tissue. At
the same time, influx of sodium (Na.sup.+) ions into cells,
followed by chloride (Cl.sup.-) ions, results in the swelling of
cells due to osmotic pressure elevation, pressuring nearby neurons
and their processes, ultimately leading to lysis (cell rupture) and
inflammatory responses. In general, this disruption of ion
homeostasis leads to excitotoxicity, cell swelling and cell death
that extends damage to adjacent tissue and expands lesions by
secondary mechanisms. There is a need for effective treatments
during the initial 24 hours to protect the stressed brain cells.
The propagation of brain damage in stroke is similar to that
observed in other forms of brain injury such as trauma and
concussions.
Beyond acute treatment, effective astrocyte function plays a key
role in broader neurorestoration--in the period 24-96 hours
following brain insult, in the period months-years in patients with
neurodegeneration such as Alzheimer's, or most generally in aged
individuals. The inability of brain cells to regenerate requires
the remaining intact brain tissue to reorganize in an attempt to
recover any loss of function. This potential for neural
reorganization is diminished in older individuals.
GPCR receptors have been suggested to mediate cardioprotective
effects. Therefore, there is potential to treat heart and
cardiovascular conditions by similar mechanisms of action via
modulation of these receptors.
There is urgent and compelling unmet medical need for more
effective treatments for brain injuries, CNS injuries, heart and
cardiovascular diseases, and related conditions, as well as
promoting neurorestoration in patients having a neurodegenerative
condition such as Alzheimer's.
SUMMARY OF THE INVENTION
It has now been found that compounds of the present invention, and
compositions thereof, are useful for treating, ameliorating, or
promoting recovery from certain conditions of the brain, central
nervous system (CNS), or cardiovascular system such as a brain
injury, a neurodegenerative condition, or cardiac ischemia. In
general, freebase forms, and pharmaceutically acceptable
compositions thereof, are useful for treating or lessening the
severity of a variety of diseases or disorders as described in
detail herein. Such compounds are represented by the chemical
structure below, denoted as compound A:
##STR00001##
Compounds of the present invention, and pharmaceutically acceptable
compositions thereof, are useful for treating a variety of
diseases, disorders or conditions, including those described
herein.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 depicts an XRPD pattern of Form A of compound A.
FIG. 2 depicts a DSC trace of Form A of compound A.
FIG. 3 depicts a TGA trace of Form A of compound A.
FIG. 4 depicts a DVS trace of Form A of compound A.
FIG. 5 depicts an XRPD pattern of Form A of compound A before (top)
and after (bottom) DVS analysis.
FIG. 6 depicts an FT-IR spectra of Form A of compound A.
FIG. 7 depicts an FT-Raman spectra of Form A of compound A.
FIG. 8 depicts a solid-state .sup.13C spectra of Form A of compound
A.
FIG. 9 depicts an optical microscope image of Form A of compound
A.
FIG. 10 depicts an XRPD pattern of Form B of compound A.
FIG. 11 depicts a DSC trace of Form B of compound A.
FIG. 12 depicts a TGA trace of Form B of compound A.
FIG. 13 depicts a DVS trace of Form B of compound A.
FIG. 14 depicts an XRPD pattern of Form B of compound A before
(top) and after (bottom) DVS analysis.
FIG. 15 depicts an FT-IR spectra of Form B of compound A.
FIG. 16 depicts an FT-Raman spectra of Form B of compound A.
FIG. 17 depicts a solid-state .sup.13C spectra of Form B of
compound A.
FIG. 18 depicts an optical microscope image of Form B of compound
A.
DETAILED DESCRIPTION OF THE INVENTION
General Description of Certain Aspects of the Invention
U.S. Pat. No. 9,789,131, filed Apr. 21, 2011 and issued Oct. 17,
2017 ("the '131 patent"), the entirety of which is hereby
incorporated herein by reference, and U.S. patent application Ser.
No. 15/670,738, filed Aug. 7, 2017 and published as US 2018/0021363
on Jan. 25, 2018 ("the '363 publication"), the entirety of which is
hereby incorporated herein by reference, describe certain
therapeutically beneficial compounds. Such compounds include
compound A:
##STR00002##
Compound A is designated as MRS4322 in the '131 patent and the
synthesis of compound A is described in detail at Example 9 of the
'131 patent, and is reproduced herein for ease of reference.
Compound A is designated as MRS4322 in the '363 publication and the
synthesis of compound A is described in detail at Example 9 of the
'363 publication, and is reproduced herein for ease of
reference.
It would be desirable to provide a solid form of compound A (e.g.,
as a freebase thereof) that imparts characteristics such as
improved aqueous solubility, stability and ease of formulation.
Accordingly, the present invention provides free base forms of
compound A.
Free Base Forms of Compound A
It is contemplated that compound A can exist in a variety of
physical forms. For example, compound A can be in solution,
suspension, or in solid form. In certain embodiments, compound A is
in solid form. When compound A is in solid form, said compound may
be amorphous, crystalline, or a mixture thereof. Exemplary solid
forms are described in more detail below.
In some embodiments, the present invention provides a form of
compound A substantially free of impurities. As used herein, the
term "substantially free of impurities" means that the compound
contains no significant amount of extraneous matter. Such
extraneous matter may include different forms of compound A,
residual solvents, or any other impurities that may result from the
preparation of, and/or isolation of, compound A. In certain
embodiments, at least about 95% by weight of a form of compound A
is present. In still other embodiments of the invention, at least
about 99% by weight of a form of compound A is present.
According to one embodiment, a form of compound A is present in an
amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8
weight percent where the percentages are based on the total weight
of the composition. According to another embodiment, a form of
compound A contains no more than about 3.0 area percent HPLC of
total organic impurities and, in certain embodiments, no more than
about 1.5 area percent HPLC total organic impurities relative to
the total area of the HPLC chromatogram. In other embodiments, a
form of compound A contains no more than about 1.0% area percent
HPLC of any single impurity; no more than about 0.6 area percent
HPLC of any single impurity, and, in certain embodiments, no more
than about 0.5 area percent HPLC of any single impurity, relative
to the total area of the HPLC chromatogram.
The structure depicted for a form of compound A is also meant to
include all tautomeric forms of compound A. Additionally,
structures depicted here are also meant to include compounds that
differ only in the presence of one or more isotopically enriched
atoms. For example, compounds having the present structure except
for the replacement of hydrogen by deuterium or tritium, or the
replacement of a carbon by a .sup.11C-, .sup.13C- or
.sup.14C-enriched carbon are within the scope of this
invention.
It has been found that compound A can exist in a variety of solid
forms. Exemplary such forms include polymorphs such as those
described herein.
As used herein, the term "polymorph" refers to the different
crystal structures into which a compound, or a salt or solvate
thereof, can crystallize.
In certain embodiments, compound A is a crystalline solid. In other
embodiments, compound A is a crystalline solid substantially free
of amorphous compound A. As used herein, the term "substantially
free of amorphous compound A" means that the compound contains no
significant amount of amorphous compound A. In certain embodiments,
at least about 95% by weight of crystalline compound A is present.
In still other embodiments of the invention, at least about 99% by
weight of crystalline compound A is present.
It has been found that compound A can exist in at least two
distinct polymorphic forms. In certain embodiments, the present
invention provides a polymorphic form of compound A referred to
herein as Form A. In certain embodiments, the present invention
provides a polymorphic form of compound A referred to herein as
Form B.
In some embodiments, compound A is amorphous. In some embodiments,
compound A is amorphous, and is substantially free of crystalline
compound A.
Form A of Compound A
In some embodiments, Form A of compound A has at least 1, 2, 3, 4
or 5 spectral peak(s) selected from the peaks listed in Table 1
below.
TABLE-US-00001 TABLE 1 XRPD Peak Positions for Form A of Compound A
Relative Relative Relative .degree.2.theta..sup.1 Intensity
.degree.2.theta. Intensity .degree.2.the- ta. Intensity 7.6 1.49
21.5 35.63 30.8 12.79 8.0 100 22.8 2.30 32.0 8.32 9.0 3.49 23.1
6.16 32.8 8.27 10.8 4.60 23.7 4.21 32.9 13.11 11.8 1.59 23.9 9.39
33.7 9.73 12.5 4.59 24.9 54.39 34.7 4.31 13.1 59.02 26.1 32.89 36.3
3.98 16.2 34.56 26.5 13.26 36.7 8.82 16.7 37.68 26.6 22.22 37.9
12.68 17.2 10.65 27.1 60.62 38.2 3.16 17.9 45.59 28.6 10.52 38.5
1.75 18.1 16.05 29.3 1.66 38.7 2.83 18.3 10.91 29.7 9.05 39.6 2.37
19.8 4.96 30.1 1.89 -- -- 21.0 30.62 30.4 1.77 -- -- .sup.1In this
and all subsequent tables, the position 2.theta. is within .+-.
0.2.
In some embodiments, Form A of compound A is characterized in that
it has one or more peaks in its X-ray powder diffraction pattern
selected from those at about 8.0 and about 13.1 degrees 2-theta. In
some embodiments, Form A of compound A is characterized in that it
has two peaks in its X-ray powder diffraction pattern selected from
those at about 8.0 and about 13.1 degrees 2-theta. As used herein,
the term "about," when used in reference to a degree 2-theta value,
refers to the stated value .+-.0.2 degree 2-theta.
In certain embodiments, the X-ray powder diffraction pattern is
substantially similar to the XRPD provided in FIG. 1.
Methods for preparing Form A of compound A are described infra.
Form B of Compound A
In some embodiments, Form B of compound A has at least 1, 2, 3, 4
or 5 spectral peak(s) selected from the peaks listed in Table 2
below.
TABLE-US-00002 TABLE 2 XRPD Peak Positions for Form B of Compound A
Relative Relative Relative .degree.2.theta..sup.1 Intensity
.degree.2.theta. Intensity .degree.2.the- ta. Intensity 4.7 2.43
20.1 88.35 29.5 4.27 7.6 3.96 21.0 42.70 29.9 3.19 9.5 14.73 21.5
68.69 30.2 6.20 10.0 10.55 23.0 2.13 30.6 7.95 10.5 7.20 23.8 53.95
31.6 4.20 13.8 20.73 24.3 8.09 32.3 1.42 14.2 10.53 24.6 3.80 32.7
5.03 14.7 40.39 25.4 5.74 33.1 4.67 15.2 6.59 25.6 8.51 33.6 3.56
15.4 14.70 25.9 35.31 35.9 7.11 16.2 4.80 26.2 20.76 37.0 2.87 17.1
24.58 26.6 16.53 37.4 1.78 17.9 58.03 27.6 7.29 39.0 1.26 18.3
12.94 28.8 25.11 -- -- 19.0 100 29.1 8.40 -- -- .sup.1In this and
all subsequent tables, the position 2.theta. is within .+-.
0.2.
In some embodiments, Form B of compound A is characterized in that
it has one or more peaks in its X-ray powder diffraction pattern
selected from those at about 19.0, about 20.1 and about 21.5
degrees 2-theta. In some embodiments, Form B of compound A is
characterized in that it has two or more peaks in its X-ray powder
diffraction pattern selected from those at about 19.0, about 20.1
and about 21.5 degrees 2-theta. In some embodiments, Form B of
compound A is characterized in that it has all three peaks in its
X-ray powder diffraction pattern selected from those at about 19.0,
about 20.1 and about 21.5 degrees 2-theta.
In some embodiments, Form B of compound A is characterized in that
it has one or more peaks in its X-ray powder diffraction pattern
selected from those at about 9.5, about 10.5 and about 13.8 degrees
2-theta. In some embodiments, Form B of compound A is characterized
in that it has two or more peaks in its X-ray powder diffraction
pattern selected from those at about 9.5, about 10.5 and about 13.8
degrees 2-theta. In some embodiments, Form B of compound A is
characterized in that it has all three peaks in its X-ray powder
diffraction pattern selected from those at about 9.5, about 10.5
and about 13.8 degrees 2-theta.
In certain embodiments, the X-ray powder diffraction pattern is
substantially similar to the XRPD provided in FIG. 10.
Methods for preparing Form B of compound A are described infra.
In some embodiments, the present invention provides compound A:
##STR00003## wherein said compound is crystalline.
In some embodiments, the present invention provides a solid form of
compound A, wherein said compound is substantially free of
amorphous compound A.
In some embodiments, the present invention provides a solid form of
compound A, wherein said compound is substantially free of
impurities.
In some embodiments, the present invention provides a solid form of
compound A, wherein said compound has one or more peaks in its XRPD
selected from those at about 8.0 and about 13.1 degrees 2-theta. In
some such embodiments, the present invention provides compound 1,
wherein said compound has two peaks in its XRPD selected from those
at about about 8.0 and about 13.1 degrees 2-theta. In some such
embodiments, the present invention provides Compound A, wherein
said compound is of Form A.
In some embodiments, the present invention provides a solid form of
compound A, wherein said compound has an XRPD substantially similar
to that depicted in FIG. 1.
In some embodiments, the present invention provides a solid form of
compound A, wherein said compound has one or more peaks in its XRPD
selected from those at about 19.0, about 20.1 and about 21.5
degrees 2-theta. In some such embodiments, the present invention
provides compound A, wherein said compound has at least two peaks
in its XRPD selected from those at about 19.0, about 20.1 and about
21.5 degrees 2-theta. In some embodiments, the present invention
provides a solid form of compound A, wherein said compound has one
or more peaks in its XRPD selected from those at about 9.5, about
10.5 and about 13.8 degrees 2-theta. In some such embodiments, the
present invention provides compound A, wherein said compound has at
least two peaks in its XRPD selected from those at about 0.5, about
10.5 and about 13.8 degrees 2-theta.
In some such embodiments, the present invention provides compound
A, wherein said compound is of Form B.
In some embodiments, the present invention provides a solid form of
compound A, wherein said compound has an XRPD substantially similar
to that depicted in FIG. 10.
In some embodiments, the present invention provides a composition
comprising a solid form of compound A and a pharmaceutically
acceptable carrier or excipient.
In some embodiments, the present invention provides a compound
selected from: compound A, Form A; and compound A, Form B.
In some embodiments, the present invention provides a method of
inhibiting or preventing the accumulation of cAMP in a patient
comprising administering to said patient a solid form of compound
A, or a pharmaceutically acceptable composition comprising the
same.
In some embodiments, the present invention provides a method of
treating an injury, disease, or condition selected from traumatic
brain injury (TBI), concussion, stroke, partial or total spinal
cord transection, malnutrition, toxic neuropathies,
meningoencephalopathies, neurodegeneration caused by a genetic
disorder, age-related neurodegeneration, vascular disease,
Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's
Disease (HD), Multiple Sclerosis (MS), amyotrophic lateral
sclerosis (ALS), chronic traumatic encephalopathy (CTE),
cardiovascular disease, autoimmune diseases, allergic diseases,
transplant rejection, graft-versus-host disease, intraocular
hypertension, glaucoma, odor sensitivity, an olfactory disorder,
type 2 diabetes and/or pain control, respiratory diseases, deficits
in CNS function, deficits in learning, deficits in cognition, otic
disorders, Meniere's disease, endolymphatic hydrops, progressive
hearing loss, dizziness, vertigo, tinnitus, collateral brain damage
associated with radiation cancer therapy, migraine treatment, sleep
disorders in the elderly, epilepsy, schizophrenia, symptoms
experienced by recovering alcoholics, damage to neurons or nerves
of the peripheral nervous system during surgery, gastrointestinal
conditions, pain mediated by the CNS, migraine, collateral brain
damage associated with radiation cancer therapy, depression, mood
or behavioral changes, dementia, erratic behavior, suicidality,
tremors, Huntington's chorea, loss of coordination of movement,
deafness, impaired speech, dry eyes, hypomimia, attention deficit,
memory loss, cognitive difficulties, vertigo, dysarthria,
dysphagia, ocular abnormalities or disorientation, or addiction;
comprising administering to a patient a solid form of compound A,
or a pharmaceutically acceptable composition comprising the same.
In some embodiments, the present invention provides a method of
treating an injury, disease, or condition selected from traumatic
brain injury (TBI), stroke, a neurodegenerative condition, or a
heart or cardiovascular disease, comprising administering to a
patient in need thereof an effective amount of an agonist of an
A.sub.3 adenosine receptor (A.sub.3R). In some embodiments, the
agonist of an A.sub.3 adenosine receptor (A.sub.3R) is a solid form
of compound A, or a pharmaceutically acceptable composition
comprising the same. In some embodiments, the agonist of an A.sub.3
adenosine receptor (A.sub.3R) is a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same. In
some embodiments, a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same, acts by dual agonism at
an A.sub.3 adenosine receptor and an A.sub.1 adenosine receptor
(A.sub.1R).
In some embodiments, the present invention provides a method of
treating an injury, disease, or condition selected from traumatic
brain injury (TBI), stroke, a neurodegenerative condition, or a
heart or cardiovascular disease, comprising administering to a
patient in need thereof an effective amount of a biased agonist,
partial agonist, or biased partial agonist of an A.sub.3 adenosine
receptor (A.sub.3R). In some embodiments, the biased agonist,
partial agonist, or biased partial agonist of an A.sub.3 adenosine
receptor (A.sub.3R) is a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same. In
some embodiments, a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same, acts by dual agonism at
an A.sub.3R and an A.sub.1R.
In some embodiments, the present invention provides a method of
treating a brain or central nervous system (CNS) injury or
condition selected from traumatic brain injury (TBI) or stroke,
comprising administering to a patient in need thereof an effective
amount of a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
In some embodiments, the present invention provides a method of
treating or ameliorating a traumatic brain injury (TBI), radiation
damage, stroke, migraine headache, a heart or cardiovascular
disease, or neurodegenerative disorder, comprising administering to
a patient in need thereof an effective amount of a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same.
In some embodiments, the present invention provides a method of
treating or ameliorating a traumatic brain injury (TBI), radiation
damage, stroke, migraine headache, a heart or cardiovascular
disease, or neurodegenerative disorder, comprising administering to
a patient in need thereof an effective amount of a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same.
In some embodiments, the present invention provides a method of
treating an injury, disease, or condition selected from traumatic
brain injury (TBI), stroke, a neurodegenerative condition, or a
heart or cardiovascular disease comprising administering to a
patient in need thereof an effective amount of a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same.
In some embodiments, the injury, disease, or condition is TBI.
In some embodiments, the TBI is selected from concussion, blast
injury, combat-related injury, or a mild, moderate or severe blow
to the head.
In some embodiments, the injury, disease, or condition is a stroke
selected from ischemic stroke, hemorrhagic stroke, subarachnoid
hemorrhage, cerebral vasospasm, or transient ischemic attacks
(TIA).
In some embodiments, neuroprotection or neurorestoration is
increased in the patient as compared with an untreated patient.
In some embodiments, the neurodegenerative disease is selected from
Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's
Disease (HD), Multiple Sclerosis (MS), amyotrophic lateral
sclerosis (ALS), chronic traumatic encephalopathy (CTE), or a
neurodegenerative condition caused by a virus, alcoholism, tumor,
toxin, or repetitive brain injuries.
In some embodiments, the neurodegenerative disease is Parkinson's
Disease.
In some embodiments, the injury, disease, or condition is
Alzheimer's Disease, migraine, brain surgery, or a neurological
side effect associated with cancer chemotherapy.
In some embodiments, the recovery period after the TBI, stroke,
cardiac ischemia, or myocardial infarction is decreased as compared
with an untreated patient.
In some embodiments, the heart or cardiovascular disease is
selected from cardiac ischemia, myocardial infarction, a
cardiomyopathy, coronary artery disease, arrhythmia, myocarditis,
pericarditis, angina, hypertensive heart disease, endocarditis,
rheumatic heart disease, congenital heart disease, or
atherosclerosis.
In some embodiments, the heart or cardiovascular disease is cardiac
ischemia or myocardial infarction.
In some embodiments, the compound or composition is administered
chronically to treat stroke, cardiac ischemia, or myocardial
infarction during the time period after the injury has occurred as
it resolves.
In some embodiments, the present invention provides a method of
increasing neuroprotection or neurorestoration in a patient in need
thereof who has suffered a TBI or stroke, comprising administering
to the patient an effective amount of a solid form of compound A,
or a pharmaceutically acceptable composition comprising the
same.
In some embodiments, the compound or pharmaceutically acceptable
salt thereof is administered orally, intravenously, or
parenterally.
In some embodiments, the compound or composition is administered
within 24 hours of the TBI or stroke.
In some embodiments, the compound or composition is administered
within 8 hours of the TBI or stroke.
In some embodiments, the compound or composition is administered at
least during the first 8-48 hours following the TBI or stroke.
In some embodiments, the present invention provides a method of
treating a heart or cardiovascular disease comprising administering
to a patient in need thereof an effective amount of a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same.
In some embodiments, the patient has suffered a cardiac ischemia or
myocardial infarction.
In some embodiments, the compound or composition increases
cardioprotection or regeneration of damaged heart tissue in the
patient.
In some embodiments, the compound or composition decreases the
recovery period after the cardiac ischemia or myocardial infarction
in the patient as compared with an untreated patient.
In some embodiments, the present invention provides a method of
treating an injury, disease, disorder, or condition selected
from:
(i) brain damage caused by radiation or collateral brain damage
associated with radiation cancer therapy or migraine treatment;
(ii) migraine headache;
(iii) a condition associated with a brain injury or a
neurodegenerative condition; or
(iv) an autoimmune disease or condition, glaucoma, an otic
disorder, progressive hearing loss, tinnitus, epilepsy, pain
control, pain mediated by the CNS, neuropathic pain, inflammatory
pain, or acute pain;
comprising administering to a patient in need thereof an effective
amount of a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
In some embodiments, the compound or composition increases
neuroprotection or neurorestoration in the patient as compared with
an untreated patient.
In some embodiments, the condition associated with a brain injury
or a neurodegenerative condition is selected from epilepsy,
migraine, collateral brain damage associated with radiation cancer
therapy, depression, mood or behavioral changes, dementia, erratic
behavior, suicidality, tremors, Huntington's chorea, loss of
coordination of movement, deafness, impaired speech, dry eyes,
hypomimia, attention deficit, memory loss, cognitive difficulties
or deficit in cognition, deficit in CNS function, deficit in
learning, vertigo, dysarthria, dysphagia, ocular abnormalities, or
disorientation.
In some embodiments, the present invention provides a method of
increasing cardioprotection or regeneration of damaged heart tissue
in a patient in need thereof who has suffered a cardiac ischemia or
myocardial infarction, comprising administering to the patient an
effective amount of a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same.
In some embodiments, the present invention provides a method for
preparing a solid form of compound A, comprising one or more steps
of removing a solvent and adding a solvent. In some embodiments, an
added solvent is the same as the solvent removed. In some
embodiments, an added solvent is different from the solvent
removed. Means of solvent removal are known in the synthetic and
chemical arts and include, but are not limited to, any of those
described herein and in the Exemplification.
In some embodiments, a method for preparing a solid form of
compound A comprises one or more steps of heating or cooling a
preparation.
In some embodiments, a method for preparing a solid form of
compound A comprises one or more steps of agitating or stirring a
preparation.
In some embodiments, a method for preparing a solid form of
compound A comprises a step of heating.
In certain embodiments, a solid form of compound A precipitates
from the mixture. In another embodiment, a solid form of compound A
crystallizes from the mixture. In other embodiments, a solid form
of compound A crystallizes from solution following seeding of the
solution (i.e., adding crystals of compound A to the solution).
A solid form of Compound A can precipitate out of the reaction
mixture, or be generated by removal of part or all of the solvent
through methods such as evaporation, distillation, filtration (ex.
nanofiltration, ultrafiltration), reverse osmosis, absorption and
reaction, by adding an anti-solvent such as heptane, by cooling or
by different combinations of these methods.
As described generally above, a solid form of compound A is
optionally isolated. It will be appreciated that a solid form of
compound A may be isolated by any suitable physical means known to
one of ordinary skill in the art. In certain embodiments,
precipitated a solid form of compound A is separated from the
supernatant by filtration. In other embodiments, precipitated solid
form of compound A is separated from the supernatant by decanting
the supernatant.
In certain embodiments, a solid form of compound A is separated
from the supernatant by filtration.
In certain embodiments, an isolated solid form of compound A is
dried in air. In other embodiments, isolated solid form of compound
A is dried under reduced pressure, optionally at elevated
temperature.
Examples of suitable solvents useful in the present invention
include, but are not limited to protic solvents, aprotic solvents,
polar aprotic solvent, or mixtures thereof. In certain embodiments,
suitable solvents include an ether, an ester, an alcohol, a ketone,
or a mixture thereof. In some embodiments, the solvent is one or
more organic alcohols. In some embodiments, the solvent is
chlorinated. In some embodiments, the solvent is an aromatic
solvent.
In certain embodiments, a suitable solvent is methanol, ethanol,
isopropanol, or acetone wherein said solvent is anhydrous or in
combination with water or heptane. In some embodiments, suitable
solvents include tetrahydrofuran, dimethylformamide,
dimethylsulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol,
n-butanol, and acetonitrile. In some embodiments, a suitable
solvent is ethanol. In some embodiments, a suitable solvent is
anhydrous ethanol. In some embodiments, the suitable solvent is
MTBE.
In some embodiments, a suitable solvent is ethyl acetate. In some
embodiments, a suitable solvent is a mixture of methanol and
methylene chloride. In some embodiments, a suitable solvent is a
mixture of acetonitrile and water. In certain embodiments, a
suitable solvent is methyl acetate, isopropyl acetate, acetone, or
tetrahydrofuran. In certain embodiments, a suitable solvent is
diethyl ether. In certain embodiments, a suitable solvent is water.
In certain embodiments, a suitable solvent is methyl ethyl ketone.
In certain embodiments, a suitable solvent is toluene.
Uses of Compounds and Pharmaceutically Acceptable Compositions
Thereof
As used herein, the terms "treatment," "treat," and "treating"
refer to reversing, alleviating, delaying the onset of, or
inhibiting the progress of a disease or disorder, or one or more
symptoms thereof, as described herein. In some embodiments,
treatment is administered after one or more symptoms have
developed. In other embodiments, treatment is administered in the
absence of symptoms. For example, treatment is administered to a
susceptible individual prior to the onset of symptoms (e.g., in
light of a history of symptoms and/or in light of genetic or other
susceptibility factors). Treatment is also continued after symptoms
have resolved, for example to prevent, delay or lessen the severity
of their recurrence.
Brain, CNS, Cardiovascular, and Other Injuries and Conditions
In some embodiments, the present invention provides a new approach
to preventing and/or treating brain damage associated with acute
brain trauma as well as longer term diseases of the brain and CNS
and heart and cardiovascular diseases and conditions. In one
aspect, the present invention provides methods of treating such
injuries, diseases, and conditions by utilizing neuroprotective and
neurorestorative effects mediated by astrocytes, which are now
understood as the key natural caretaker cell of neurons, as well as
the astrocyte mitochondria, which supply a significant portion of
the brain's energy. In another aspect, the present invention
provides methods of treating such injuries, diseases, and
conditions by cardioprotective and regenerative effects mediated by
A.sub.3R receptors. Regarding neuroprotective and neurorestorative
effects, without wishing to be bound by theory, it is believed that
selective enhancement of astrocyte energy metabolism mediated by
A.sub.3R and/or P2Y.sub.1 receptors promotes astrocyte caretaker
functions, such as their neuroprotective and neurorestorative
functions, in turn enhancing the resistance of neurons and other
cells to both acute injury and long term stress. In some cases, it
may be advantageous to achieve biased, i.e., selective or
preferential, of one or more pathways mediated by A.sub.3R and/or
P2Y.sub.1 and/or A.sub.1R receptors wherein one or more undesired
pathways are not activated, or activated to a lesser degree. In
addition to or as an alternative to astrocytes, neuroprotective or
neurorestorative function of glia, microglia, neurons, endothelium
cells and other brain and/or CNS cell types may be activated.
Accordingly, in one aspect, the present invention provides
compounds and methods of use thereof for treating, ameliorating, or
promoting recovery from certain conditions of the brain or central
nervous system (CNS) such as brain injuries, for example by
increasing neuroprotection and/or neurorestorative effects mediated
by astrocytes, glia, microglia, neurons, endothelium cells or other
cells of the brain and/or CNS, comprising administering to a
patient in need thereof an effective amount of a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same.
Astrocytes play key roles in supporting and protecting neurons and
they critically affect the outcome of brain injuries that cause
brain damage, such as ischemic injuries. The central role astrocyte
mitochondria themselves play in these brain functions is less well
appreciated. For example, inhibition of astrocyte mitochondria
increases swelling and leads to necrotic cell death. Neurons are
permanently injured by recurrent spreading depolarizations only if
astrocyte mitochondrial function fails, and astrocyte mitochondria
are required for reduction of pathophysiological elevations of
extracellular K.sup.+, which initiate spreading depolarizations.
Activation of purinergic receptors on astrocytes results in
increased mitochondrial Ca.sup.2+ that enhances mitochondrial
citric acid cycle function and increases respiration and ATP
production. Accordingly, in one aspect, the present invention
relates to the discovery that activation of astrocyte purinergic
receptors enhances brain cell survival signalling pathways,
enabling both astrocyte and neuronal viability during oxidative
stress. Furthermore, activated astrocytes generate and supply
reduced glutathione, a key antioxidant that aids in the resistance
of both astrocytes and neurons to oxidative stress. Thus, in one
aspect, the present invention provides a method of modulating
astrocyte purinergic receptors to promote survival and viability of
one or more cell types in the brain of a patient after oxidative
stress, such as oxidative stress caused by a brain injury,
ischemia-reperfusion or a neurodegenerative condition, comprising
administering to a patient in need thereof a solid form of compound
A, or a pharmaceutically acceptable composition comprising the
same.
In some embodiments, activation of astrocytes is achieved through
contacting with a disclosed compound one or more purinergic
receptors such as adenosine receptors (ARs), for example those
associated with or expressed by astrocytes, thus modulating the
activity of the one or more receptors. In some embodiments, through
effects on adenosine receptors such as A.sub.1, A.sub.2A, A.sub.2B
and A.sub.3 on astrocytes, the compound activates astrocytes to
treat one or more disclosed diseases or conditions. In some
embodiments, after administration to a patient in need thereof, a
disclosed compound influences one or more functions such as
glutamate uptake, reactive gliosis, swelling, and release of
neurotrophic and neurotoxic factors having an impact on metabolic
stress and its consequences, thus treating one or more diseases or
conditions. In some embodiments, the compound is an AR agonist. In
some embodiments, the purinergic receptor is an A.sub.3 adenosine
receptor (A.sub.3R). In some embodiments, the compound is an
A.sub.3R agonist. In some embodiments, the compound is a partial
agonist or biased agonist or biased partial agonist, at an A.sub.3
receptor (A.sub.3R), such as a human A.sub.3 receptor (hA3R). In
some embodiments, the compound is a biased antagonist at an A.sub.3
receptor. In some embodiments, the compound acts by dual agonism at
an A.sub.3R and an A.sub.1R. In some embodiments, the compound is a
solid form of compound A, or a pharmaceutically acceptable
composition comprising the same.
P2Y receptors are G-protein-coupled receptors and different
subtypes of these receptors have important roles in processes such
as synaptic communication, cellular differentiation, ion flux,
vasodilation, blood brain barrier permeability, platelet
aggregation and neuromodulation. Characterized members of the
purinergic P2Y receptor family include the mammalian P2Y.sub.1,
P2Y.sub.11, P2Y.sub.12 and P2Y.sub.13 receptors, which bind to
adenine nucleotides; the P2Y.sub.4, P2Y.sub.6, and P2Y.sub.14
receptors, that bind to uracil nucleotides; and the P2Y.sub.2 and
rodent P2Y.sub.4 receptors, which have mixed selectivity. In some
embodiments, activation of astrocytes is achieved through
contacting with a disclosed compound one or more purinergic
receptors such as P2Y receptors, for example those associated with
or expressed by astrocytes, thus modulating the activity of the one
or more receptors. In some embodiments, through effects on P2Y
receptors such as P2Y.sub.1, P2Y.sub.11, P2Y.sub.12 and P2Y.sub.13
receptors associated with or expressed by astrocytes, the compound
activates astrocytes to treat one or more disclosed diseases or
conditions. In some embodiments, the P2Y receptor is a P2Y.sub.1
receptor. In some embodiments, the P2Y.sub.1 receptor is located on
intracellular mitochondrial membranes. In some embodiments, the
compound is a P2Y agonist. In some embodiments, the compound is a
P2Y.sub.1 agonist, e.g. at a human P2Y.sub.1 receptor. In some
embodiments, the compound is a biased agonist, partial agonist, or
biased partial agonist at a P2Y.sub.1 receptor, such as a human
P2Y.sub.1 receptor. In some embodiments, the compound is a biased
antagonist at a P2Y.sub.1 receptor. In some embodiments, the
compound is a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
In another aspect, the present invention provides a method of
treating or ameliorating a brain injury, such as a brain injury
resulting from a TBI or progressive neurodegenerative disorder, in
a patient in need thereof, comprising administering to the patient
an effective amount of a disclosed compound. In some embodiments,
the subject has suffered a TBI, concussion, stroke, partial or
total spinal cord transection, or malnutrition. In other
embodiments, the subject has suffered toxic neuropathies,
meningoencephalopathies, neurodegeneration caused by a genetic
disorder, age-related neurodegeneration, or a vascular disease; or
another disease disclosed in U.S. Pat. No. 8,691,775, which is
hereby incorporated by reference. In some embodiments, the present
invention provides a method of treating or ameliorating a brain
injury, such as a brain injury resulting from a TBI or progressive
neurodegenerative disorder, in a patient in need thereof,
comprising administering to the patient an effective amount of an
A.sub.3R agonist. In other embodiments, the present invention
provides a method of treating or ameliorating a brain injury, such
as a brain injury resulting from a TBI or progressive
neurodegenerative disorder, in a patient in need thereof,
comprising administering to the patient an effective amount of a
P2Y.sub.1 agonist. In some embodiments, the compound is a biased
agonist, partial agonist, or biased partial agonist at an A.sub.3
receptor. In some embodiments, the compound acts by dual agonism at
an A.sub.3R and an A.sub.1R. In some embodiments, the compound is a
biased agonist, partial agonist, or biased partial agonist or
antagonist at a P2Y.sub.1 receptor. In some embodiments, the
compound is a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
In another aspect, the present invention provides a method of
promoting or increasing neuroprotection, neurorestoration, or
neuroregeneration in a patient suffering from a disease or
condition, comprising administering to the patient an effective
amount of a disclosed compound, for example a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same. In some embodiments, the patient is suffering from a
neurodegenerative disease or condition. In some embodiments, the
patient has suffered a TBI.
In another aspect, the present invention provides a method of
promoting astrocyte-mediated neuroprotection or neurorestoration in
a patient in need thereof, comprising administering to the patient
an effective amount of a disclosed compound. In some embodiments,
the present invention provides a method of promoting
astrocyte-mediated neuroprotection or neurorestoration in a patient
in need thereof, comprising administering to the patient an
effective amount of an A.sub.3R agonist. In other embodiments, the
present invention provides a method of promoting astrocyte-mediated
neuroprotection or neurorestoration in a patient in need thereof,
comprising administering to the patient an effective amount of a
P2Y.sub.1 agonist. In some embodiments, the compound is a biased
agonist, partial agonist, or biased partial agonist or antagonist
at an A.sub.3 receptor. In some embodiments, the compound acts by
dual agonism at an A.sub.3R and an A.sub.1R. In some embodiments,
the compound is a biased agonist, partial agonist, or biased
partial agonist or antagonist at a P2Y.sub.1 receptor. In some
embodiments, the compound is a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same.
In another aspect, the present invention provides a method of
promoting survival of neurons, glial cells, endothelial cells or
other brain cells, such as those in an ischemic penumbra in a
patient in need thereof, comprising administering to the patient an
effective amount of a compound disclosed herein. In some
embodiments, the present invention provides a method of promoting
survival of neurons, glial cells, or other brain cells, such as
those in an ischemic penumbra in a patient in need thereof,
comprising administering to the patient an effective amount of an
A.sub.3R agonist. In some embodiments, the present invention
provides a method of promoting survival of neurons, glial cells,
endothelial cells or other brain cells, such as those in an
ischemic penumbra in a patient in need thereof, comprising
administering to the patient an effective amount of a P2Y.sub.1
agonist. In some embodiments, the compound is a biased agonist,
partial agonist, or biased partial agonist or antagonist at an
A.sub.3 receptor. In some embodiments, the compound acts by dual
agonism at an A.sub.3R and an A.sub.1R. In some embodiments, the
compound is a biased agonist, partial agonist, or biased partial
agonist or antagonist at a P2Y.sub.1 receptor. In some embodiments,
the compound is a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
In further embodiments, the patient has or is at risk of acquiring
a brain injury such as those below. Accordingly, methods of
treating the conditions discussed below are also provided.
Traumatic Brain Injuries
Traumatic brain injuries (TBI) are a distressingly common medical
condition and are predicted to become the third major cause of
global morbidity and mortality by 2020. There are no approved
treatments for TBI, and most TBI patients are discharged from the
hospital with no pharmacological treatment (Witt 2006). Repetitive
TBI such as concussions can trigger age-associated
neurodegeneration that results in a range of symptoms and
disabilities over decades (McKee 2013). TBIs can happen through
sports-related injuries, motor vehicle accidents, falls, explosive
impacts, physical assaults, etc. Injuries range widely in their
complexity and severity, from "mild" concussions with brief
alterations in mental status, cognitive difficulties, or loss of
consciousness to "severe" with prolonged periods of unconsciousness
and/or amnesia after the injury. In the U.S., approximately 1.7
million people have an injury resulting in a TBI annually and seek
medical intervention (USCSF and CDC), and the CDC estimates that
1.6 to 3.8 million additional concussion incidents occur in sports
and other recreational pursuits annually that do not present to
hospital or emergency departments. (CDC; Langlois 2006)
Approximately 5-10% of athletes will receive a concussion each
sport season. (Sports Concussion Institute 2012) Football is the
sport with the highest concussion risk for males (75% chance for
concussion), while soccer has the highest concussion risk for
females (50% chance for concussion). TBI is the leading cause of
death and disability in children and young adults (CDC) and the
most commonly received military-related injury; approximately 20%
of U.S. Service Members deployed since 2003 have sustained at least
one TBI. (Chronic Effects of Neurotrauma Consortium (CENC); Warden
2006; Scholten 2012; Taylor 2012; Gavett 2011; Guskiewicz 2005;
Omalu 2005) Total TBI-related indirect and direct medical costs are
estimated at $77 billion annually (UCSF and CDC). At least 5
million Americans require ongoing daily support in performing
activities as a result of TBI (CDC and Thurman 1999).
Activation of astrocytes according to the present invention
represents a new treatment option for such conditions. Accordingly,
provided herein in one aspect is a method of treating TBI or
promoting recovery from TBI, comprising administering to a patient
in need thereof an effective amount of a disclosed compound. In
some embodiments, the TBI is selected from traumatic injuries to
the brain (such as concussion, blast injury, combat-related injury)
or spinal cord (such as partial or total spinal cord transection).
In some embodiments, the TBI results from a mild, moderate, or
severe blow to the head, comprises an open or closed head wound, or
results from a penetrating or non-penetrating blow to the head. In
some embodiments, the present invention provides a method of
treating TBI or promoting recovery from TBI, comprising
administering to a patient in need thereof an effective amount of
an A.sub.3R agonist. In some embodiments, the present invention
provides a method of treating TBI or promoting recovery from TBI,
comprising administering to a patient in need thereof an effective
amount of a P2Y.sub.1 agonist. In some embodiments, the compound is
a biased agonist, partial agonist, or biased partial agonist or
antagonist at an A.sub.3 receptor. In some embodiments, the
compound acts by dual agonism at an A.sub.3R and an A.sub.1R. In
some embodiments, the compound is a biased agonist, partial
agonist, or biased partial agonist or antagonist at a P2Y.sub.1
receptor. In some embodiments, the compound is a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same.
Stroke
A stroke occurs when a blood vessel that transports oxygen and
nutrients to the brain is disrupted due to an ischemic blockage or
from the hemorrhagic rupture of a blood vessel in the brain,
causing neurons, glia and endothelial cells in the disrupted region
of the brain to die. The outcome of the stroke depends upon the
location and breadth of damage, and the impacts of that damage are
observed in the body functions regulated by the damaged brain
region. Strokes can cause unilateral or bilateral paralysis, speech
and language disabilities, memory loss, behavioural changes, and
even death. Stroke is the fourth leading cause of death in the
United States and is a major cause of adult disability. Each year,
.about.800,000 people experience a new or recurrent stroke. Each
day, over 2000 Americans will have a stroke, resulting in death in
over 400 of these incidents. Stroke accounted for .about.1 of every
19 deaths in the United States in 2010. An estimated 6.8 million
Americans .gtoreq.20 years of age has had a stroke. (AHA and Go
2014) As of 2010, the annual direct and indirect cost of stroke was
estimated at $36.5 billion. Within minutes of a stroke, the lack of
blood flow will permanently damage a core of brain tissue. Between
this damaged core and normal brain tissue is a region of tissue
known as the penumbra--tissue that is under gradated stress from
lessened blood flow and some disruption of energy metabolism. Over
the first 24-48 hours following a stroke incident, the stress on
neuronal and glia cells in the penumbra resolves either with some
recovery or further cell death.
In one aspect, the present invention provides a method of
neuroprotective therapy in a stroke patient, comprising
administering to a patient in need thereof an effective amount of a
disclosed compound. In some embodiments, such therapy salvages as
much of the penumbra as possible, and/or limits further acute
tissue damage, and/or promotes neuron recovery. In another aspect
is provided a method of treating stroke or promoting recovery from
stroke, comprising administering to a patient in need thereof an
effective amount of a disclosed compound. In another aspect is
provided a method of promoting or increasing neuroprotection,
neuroregeneration, or neurorestoration in a patient who has
suffered a stroke, comprising administering to the patient an
effective amount of a disclosed compound. In another aspect is
provided a method of treating stroke or promoting recovery from
stroke, comprising administering to a patient in need thereof an
effective amount of an A.sub.3R agonist. In some embodiments, the
present invention provides a method of treating stroke or promoting
recovery from stroke, comprising administering to a patient in need
thereof an effective amount of a P2Y.sub.1 agonist. In some
embodiments, the compound is a biased agonist, partial agonist, or
biased partial agonist or antagonist at an A.sub.3 receptor. In
some embodiments, the compound acts by dual agonism at an A.sub.3R
and an A.sub.1R. In some embodiments, the compound is a biased
agonist, partial agonist, or biased partial agonist or antagonist
at a P2Y.sub.1 receptor. In some embodiments, the compound is a
solid form of compound A, or a pharmaceutically acceptable
composition comprising the same.
In some embodiments, the stroke is selected from selected from
ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage,
cerebral vasospasm, or transient ischemic attacks (TIA). In some
embodiments, the stroke is ischemic. In some embodiments, the
stroke is hemorrhagic. In some embodiments, the compound is
administered within 48 hours of the stroke. In some embodiments,
the compound is administered within 24 hours of the stroke. In some
embodiments, the compound is administered within 16 hours of the
stroke. In some embodiments, the compound is administered within 8,
4, 2, or 1 hours of the stroke. In some embodiments, the compound
is administered for at least the first 1-72 hours following the
stroke. In some embodiments, the compound is administered for at
least the first 8-52 hours following the stroke. In some
embodiments, the compound is administered for at least the first
8-48 hours following the stroke. In some embodiments, the compound
is administered for at least the first 24-48 hours following the
stroke. In some embodiments, the compound is administered
chronically to treat the stroke as it occurs. In some embodiments,
the compound is administered chronically to treat Transient
Ischemic Attacks (TIA).
In some embodiments, the compound is administered chronically to
treat ischemic stroke, hemorrhagic stroke, a subarachnoid
hemorrhage, cerebral vasospasm, transient ischemic attacks (TIA),
or treat a patient who is at an increased risk for a stroke, such
as a patient who has had a stroke in the past and is at risk for a
further stroke, such as a patient over the age of 40, 45, 50, 55,
60, 65, 70, 75, or 80 years of age.
In some embodiments, the compound treats an ischemia-reperfusion
injury caused by the stroke.
Neurodegenerative Diseases
Neurodegenerative diseases are incurable, progressive, and
ultimately debilitating syndromes resulting from the progressive
degeneration and/or death of neurons in the brain and spinal cord.
Neurodegeneration results in movement (ataxias) and/or cognitive
function (dementias) disorders, and includes a spectrum of diseases
such as Alzheimer's Disease (AD), Parkinson's Disease (PD),
Huntington's Disease (HD), Multiple Sclerosis (MS), amyotrophic
lateral sclerosis (ALS), and chronic traumatic encephalopathy
(CTE). While many neurodegenerative diseases are principally
genetic in origin, other causes can include viruses, alcoholism,
tumors or toxins, and as is now clear, repetitive brain
injuries.
Neurons accumulate cellular damage over time due to the foregoing
factors, which is generally considered the reason why many
neurodegenerative diseases associated with prolonged cellular
stress, such as Alzheimer's disease and Parkinson's disease, occur
in aged individuals. Dementias represent the predominant outcome of
neurodegenerative diseases with AD representing approximately
60-70% of cases. (Kandale 2013) As discussed above, activation of
neuroprotective and neurorestorative mechanisms can ameliorate the
progression of one or more neurodegenerative diseases. Accordingly,
in one aspect the present invention provides a method of treating a
neurodegenerative disease or promoting recovery from a
neurodegenerative disease, comprising administering to a patient in
need thereof an effective amount of a solid form of compound A, or
a pharmaceutically acceptable composition comprising the same.
In one aspect, the present invention provides a method of promoting
neuroprotection or neurorestoration in a patient suffering from a
neurodegenerative disease, comprising administering to the patient
an effective amount of a disclosed compound. In some embodiments is
provided a method of promoting neuroprotection or neurorestoration
in a patient suffering from a neurodegenerative disease, comprising
administering to the patient an effective amount of an A.sub.3R
agonist. In other embodiments is provided a method of promoting
neuroprotection or neurorestoration in a patient suffering from a
neurodegenerative disease, comprising administering to the patient
an effective amount of a P2Y.sub.1 agonist. In some embodiments,
the compound is a biased agonist, partial agonist, or biased
partial agonist or antagonist at an A.sub.3 receptor. In some
embodiments, the compound acts by dual agonism at an A.sub.3R and
an A.sub.1R. In some embodiments, the compound is a biased agonist,
partial agonist, or biased partial agonist or antagonist at a
P2Y.sub.1 receptor. In some embodiments, the compound is a solid
form of compound A, or a pharmaceutically acceptable composition
comprising the same.
Alzheimer's Disease (AD)
An estimated 5.2 million Americans of all ages had AD in 2014; 11%
of the population age 65 and older have AD. (Alzheimer's
Association) By 2050, the number of people age 65 and older with AD
is projected to nearly triple to a projected 13.8 million. In the
U.S., the cost of providing care for AD patients is about $214
billion per year; 70% of this cost is covered by Medicare and
Medicaid. The current trends would project these costs to grow to
$1.2 trillion per year by 2050.
Activation of astrocytes and promoting neuroprotection and
neurorestoration according to the present invention represents a
new treatment option for AD. Accordingly, provided herein in one
aspect is a method of treating AD or promoting neuroprotection or
neurorestoration in a patient suffering from AD, comprising
administering to the patient an effective amount of a compound
disclosed herein. In some embodiments, the present invention
provides a method of treating AD or promoting neuroprotection or
neurorecovery in a patient suffering from AD, comprising
administering to the patient an effective amount of an A.sub.3R
agonist. In some embodiments, the present invention provides a
method of treating AD or promoting neuroprotection or neurorecovery
in a patient suffering from AD, comprising administering to the
patient an effective amount of a P2Y.sub.1 agonist. In some
embodiments, the compound is a biased agonist, partial agonist, or
biased partial agonist or antagonist at an A.sub.3 receptor. In
some embodiments, the compound acts by dual agonism at an A.sub.3R
and an A.sub.1R. In some embodiments, the compound is a biased
agonist, partial agonist, or biased partial agonist or antagonist
at a P2Y.sub.1 receptor. In some embodiments, the compound is a
solid form of compound A, or a pharmaceutically acceptable
composition comprising the same.
Parkinson's Disease (PD)
As many as one million Americans live with PD, and each year
approximately 60,000 Americans are newly diagnosed not including
the thousands of cases that go undetected. (Parkinson's Disease
Foundation) The total combined direct and indirect cost of PD,
including medical treatment, social security payments and lost
income, is estimated to be nearly $25 billion per year in the
United States. (Parkinson's Disease Foundation and Huse 2005)
Activation of neuroprotection and neurorestoration according to the
present invention represents a new treatment option for PD.
Accordingly, provided herein in one aspect is a method of treating
PD or promoting neuroprotection or neurorestoration in a patient
suffering from PD, comprising administering to the patient an
effective amount of a disclosed compound. In some embodiments, the
present invention provides a method of treating PD or promoting
neuroprotection or neurorecovery in a patient suffering from PD,
comprising administering to the patient an effective amount of an
A.sub.3R agonist. In some embodiments, the present invention
provides a method of treating PD or promoting neuroprotection or
neurorecovery in a patient suffering from PD, comprising
administering to the patient an effective amount of a P2Y.sub.1
agonist. In some embodiments, the compound is a biased agonist,
partial agonist, or biased partial agonist or antagonist at an
A.sub.3 receptor. In some embodiments, the compound acts by dual
agonism at an A.sub.3R and an A.sub.1R. In some embodiments, the
compound is a biased agonist, partial agonist, or biased partial
agonist or antagonist at a P2Y.sub.1 receptor. In some embodiments,
the compound is a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
Multiple Sclerosis (MS)
More than 400,000 people in the United States have MS. In young
adults, MS represents the most prevalent disease of the central
nervous system. (Multiple Sclerosis Foundation) There is potential
for astrocytes to reverse the destruction of nerve cell myelin
coatings that is caused by MS by their neurorestorative effects and
promotion of healing in the damaged CNS of MS patients.
Activation of neuroprotection and neurorestoration in the CNS
according to the present invention thus represents a new treatment
option for MS. Accordingly, provided herein in one aspect is a
method of treating MS or promoting neuroprotection or
neurorestoration in a patient suffering from MS, comprising
administering to the patient an effective amount of a disclosed
compound. In some embodiments, the present invention provides a
method of treating MS or promoting neuroprotection or neurorecovery
in a patient suffering from MS, comprising administering to the
patient an effective amount of an A.sub.3R agonist. In some
embodiments, the present invention provides a method of treating MS
or promoting neuroprotection or neurorecovery in a patient
suffering from MS, comprising administering to the patient an
effective amount of a P2Y.sub.1 agonist. In some embodiments, the
compound is a biased agonist, partial agonist, or biased partial
agonist or antagonist at an A.sub.3 receptor. In some embodiments,
the compound acts by dual agonism at an A.sub.3R and an A.sub.1R.
In some embodiments, the compound is a biased agonist, partial
agonist, or biased partial agonist or antagonist at a P2Y.sub.1
receptor. In some embodiments, the compound is a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same.
Amyotrophic Lateral Sclerosis (ALS)/Lou Gehrig's Disease
Approximately 5,600 people in the U.S. are diagnosed with ALS each
year; as many as 30,000 Americans may have the disease
concurrently. (ALS Association) Activation of astrocytes can
provide stimulation of recovery and repair of the neurons and their
connections in an ALS patient.
Accordingly, provided herein in one aspect is a method of treating
ALS or promoting neuroprotection or neurorestoration in a patient
suffering from ALS, comprising administering to the patient an
effective amount of a disclosed compound. Also provided in other
embodiments is a method of stimulating recovery and repair of the
neurons and their connections in an ALS patient, comprising
administering to the patient an effective amount of a compound
disclosed herein. In some embodiments, the present invention
provides a method of treating ALS or promoting neuroprotection or
neurorecovery in a patient suffering from ALS, comprising
administering to the patient an effective amount of an A.sub.3R
agonist. In some embodiments, the present invention provides a
method of treating ALS or promoting neuroprotection or
neurorecovery in a patient suffering from ALS, comprising
administering to the patient an effective amount of a P2Y.sub.1
agonist. In some embodiments, the compound is a biased agonist,
partial agonist, or biased partial agonist or antagonist at an
A.sub.3 receptor In some embodiments, the compound acts by dual
agonism at an A.sub.3R and an A.sub.1R. In some embodiments, the
compound is a biased agonist, partial agonist, or biased partial
agonist or antagonist at a P2Y.sub.1 receptor. In some embodiments,
the compound is a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
Chronic Traumatic Encephalopathy (CTE)
CTE (a form of tauopathy) is a progressive neurodegenerative
disease found in individuals who have suffered one or more (often
multiple, or repeated over the course of time) severe blows to the
head. CTE is most often diagnosed in professional athletes in
American football, soccer, hockey, professional wrestling, stunt
performing, bull riding and rodeo performing, motocross, and other
contact sports who have experienced brain trauma and/or repeated
concussions. A subset of CTE sufferers have chronic traumatic
encephalomyopathy (CTEM), which is characterized by motor neuron
disease symptoms that mimic ALS. Progressive muscle weakness and
motor and gait abnormalities are believed to be early signs of
CTEM. First stage symptoms of CTE include progressive attention
deficit, disorientation, dizziness, and headaches. Second stage
symptoms comprise memory loss, social instability, erratic
behavior, and poor judgment. In third and fourth stages, patients
suffer progressive dementia, slowed movements, tremors, hypomimia,
vertigo, speech impediments, hearing loss, and suicidality, and may
further include dysarthria, dysphagia, and ocular abnormalities,
e.g. ptosis.
Accordingly, provided herein in one aspect is a method of treating
or preventing CTE or promoting neuroprotection or neurorestoration
in a patient suffering from CTE, comprising administering to the
patient an effective amount of a disclosed compound. Also provided
in other embodiments is a method of stimulating recovery and repair
of the neurons and their connections in a CTE patient, comprising
administering to the patient an effective amount of a disclosed
compound. In some embodiments, the compound treats one or more
symptoms of first stage, second stage, third stage, or fourth stage
CTE. In some embodiments, the present invention provides a method
of treating CTE or promoting neuroprotection or neurorecovery in a
patient suffering from CTE, comprising administering to the patient
an effective amount of an A.sub.3R agonist. In some embodiments,
the present invention provides a method of treating CTE or
promoting neuroprotection or neurorecovery in a patient suffering
from CTE, comprising administering to the patient an effective
amount of a P2Y.sub.1 agonist. In some embodiments, the compound is
a biased agonist, partial agonist, or biased partial agonist or
antagonist at an A.sub.3 receptor. In some embodiments, the
compound acts by dual agonism at an A.sub.3R and an A.sub.1R. In
some embodiments, the compound is a biased agonist, partial
agonist, or biased partial agonist or antagonist at a P2Y.sub.1
receptor. In some embodiments, the compound is a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same.
On a microscopic scale the pathology includes neuronal death, tau
deposition, TAR DNA-binding Protein 43 (TDP 43) beta-amyloid
deposition, white matter changes, and other abnormalities. Tau
deposition includes the increasing presence of dense
neurofibrillary tangles (NFT), neurites, and glial tangles, which
are made up of astrocytes and other glial cells. Thus, in some
embodiments, the method treats, enhances clearance or prevents
neuronal death, tau deposition, TAR DNA-binding Protein 43 (TDP 43)
beta-amyloid deposition, white matter changes, and other
abnormalities associated with CTE.
In some embodiments, the present invention provides long-term
administration of a compound disclosed herein, such as a biased
agonist, partial agonist, or biased partial agonist of A.sub.3R, or
a dual agonist at an A.sub.3R and an A.sub.1R, or a biased agonist,
partial agonist, or biased partial agonist of P2Y.sub.1, to treat a
neurodegenerative disease, such as those discussed above and
below.
Cardiovascular Diseases
Disclosed compounds are also useful in treating a variety of
cardiovascular diseases and conditions. In some embodiments, the
present invention provides a method of treating a heart (cardiac)
or cardiovascular disease, such as cardiac ischemia, myocardial
infarction, a cardiomyopathy, coronary artery disease, arrhythmia,
myocarditis, pericarditis, angina, hypertensive heart disease,
endocarditis, rheumatic heart disease, congenital heart disease, or
atherosclerosis, comprising administering an effective amount of a
disclosed compound to a patient in need thereof, such as a solid
form of compound A, or a pharmaceutically acceptable composition
comprising the same. In some embodiments, a disclosed compound
provides for modulation of ATP-sensitive potassium channels, for
example via biased agonism, partial agonism, or biased partial
agonism at an A.sub.3R receptor, or dual agonism at an A.sub.3R and
an A.sub.1R.
In some embodiments, the heart or cardiovascular disease is cardiac
ischemia or myocardial infarction.
In some embodiments, the present invention provides a method of
promoting or increasing cardioprotection, cardiorestoration, or
cardioregeneration in a patient suffering from a heart (cardiac) or
cardiovascular disease or condition, comprising administering to
the patient an effective amount of a disclosed compound, for
example a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
In some embodiments, the heart (cardiac) or cardiovascular disease
from which the patient is suffering is cardiac ischemia, myocardial
infarction, a cardiomyopathy, coronary artery disease, arrhythmia,
myocarditis, pericarditis, angina, hypertensive heart disease,
endocarditis, rheumatic heart disease, congenital heart disease, or
atherosclerosis.
In some embodiments, a disclosed compound provides for modulation
of ATP-sensitive potassium channels, for example via biased
agonism, partial agonism, or biased partial agonism at an A.sub.3R
receptor, or dual agonism at an A.sub.3R and an A.sub.1R.
Other Diseases
Compounds that modulate beneficial effects such as neuroprotection,
for example by increasing astrocyte mitochondrial activity, also
have the potential to treat a variety of other diseases. For
example, due to the role of astrocytes in neuroprotection disclosed
in the present invention, activation of astrocytes, for example via
modulation of A.sub.3R and/or a P2Y.sub.1 receptor, may be useful
in treating various diseases and conditions discussed below.
Accordingly, in some embodiments, the present invention provides a
method of treating neurodegeneration in a patient suffering from a
disease or condition, comprising administering to the patient an
effective amount of a disclosed compound, for example a solid form
of compound A, or a pharmaceutically acceptable composition
comprising the same.
In some embodiments, the present invention provides a method of
promoting or increasing neuroprotection, neurorestoration, or
neuroregeneration in a patient suffering from a disease or
condition, comprising administering to the patient an effective
amount of a disclosed compound, for example a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same.
In some embodiments, the disease or condition is selected from
autoimmune diseases, allergic diseases, and/or transplant rejection
and graft-versus-host disease (for the use of certain nucleoside
and nucleotide compounds in treating these conditions, see, for
example, WO 2007/20018, hereby incorporated by reference). In other
embodiments, the disease or condition is selected from intraocular
hypertension and/or glaucoma (for the use of certain nucleoside and
nucleotide compounds in treating these conditions, see, for
example, WO 2011/77435, hereby incorporated by reference). In other
embodiments, the disease or condition is selected from odor
sensitivity and/or an olfactory disorder (for the use of certain
nucleoside and nucleotide compounds in treating these conditions,
see, for example, EP1624753, hereby incorporated by reference). In
other embodiments, the disease or condition is selected from type 2
diabetes and/or pain control (for the use of certain nucleoside and
nucleotide compounds in treating these conditions, see, for
example, US 2010/0256086, hereby incorporated by reference).
In other embodiments, the disease or condition is selected from
respiratory diseases and/or cardiovascular (CV) diseases (for the
use of certain nucleoside and nucleotide compounds in treating
these conditions, see, for example, FASEB J. (2013) 27:1118.4
(abstract of meeting), hereby incorporated by reference). In other
embodiments, the disease or condition is selected from deficits in
CNS function, deficits in learning and/or deficits in cognition
(for the use of certain nucleoside and nucleotide compounds in
treating these conditions, see, for example,
Neuropsychopharmacology. 2015 January; 40(2):305-14. doi:
10.1038/npp.2014.173. Epub 2014 Jul. 15. "Impaired cognition after
stimulation of a P2Y.sub.1 receptor in the rat medial prefrontal
cortex," Koch, H. et al. PMID: 25027332, hereby incorporated by
reference). In other embodiments, the disease or condition is
selected from a neurodegenerative disease such as Alzheimer's
disease, Parkinson's disease, Huntington's disease, prion disease,
and/or amyotrophic lateral sclerosis (for the use of certain
nucleoside and nucleotide compounds in treating these conditions,
see, for example, U.S. Pat. No. 8,691,775, hereby incorporated by
reference). In other embodiments, the disease or condition is
selected from otic disorders, Meniere's disease, endolymphatic
hydrops, progressive hearing loss, dizziness, vertigo, tinnitus,
collateral brain damage associated with radiation cancer therapy,
and/or migraine treatment (for the use of certain nucleoside and
nucleotide compounds in treating these conditions, see, for
example, US 2009/0306225; UY31779; and U.S. Pat. No. 8,399,018,
each of which is hereby incorporated by reference). In other
embodiments, the disease or condition is selected from pathological
sleep perturbations, depression, sleep disorders in the elderly,
Parkinson's disease, Alzheimer's disease, epilepsy, schizophrenia,
and/or symptoms experienced by recovering alcoholics (for the use
of certain nucleoside and nucleotide compounds in treating these
conditions, see, for example, US 2014/0241990, hereby incorporated
by reference). In other embodiments, the disease or condition is
selected from damage to neurons or nerves of the peripheral nervous
system during surgery (for the use of certain nucleoside and
nucleotide compounds in treating these conditions, see, for
example, U.S. Pat. No. 8,685,372, hereby incorporated by
reference). In other embodiments, the disease or condition is a
cancer such as prostate cancer (for the use of certain nucleoside
and nucleotide compounds in treating these conditions, see, for
example, Biochem Pharmacol. 2011 Aug. 15; 82(4): 418-425.
doi:10.1016/j.bcp.2011.05.013. "Activation of the P2Y1 Receptor
Induces Apoptosis and Inhibits Proliferation of Prostate Cancer
Cells," Qiang Wei et al., hereby incorporated by reference). In
other embodiments, the disease or condition is selected from one or
more gastrointestinal conditions such as constipation and/or
diarrhea (for the use of certain nucleoside and nucleotide
compounds in treating these conditions, see, for example, Acta
Physiol (Oxf). 2014 December; 212(4):293-305. doi:
10.1111/apha.12408. "Differential functional role of purinergic and
nitrergic inhibitory cotransmitters in human colonic relaxation,"
Mane N1, Gil V, Martinez-Cutillas M, Clave P, Gallego D, Jimenez
M.; and Neurogastroenterol. Motil. 2014 January; 26(1):115-23. doi:
10.1111/nmo.12240. Epub 2013 Oct. 8. "Calcium responses in
subserosal interstitial cells of the guinea-pig proximal colon,"
Tamada H., Hashitani H. PMID: 24329947, hereby incorporated by
reference). In other embodiments, the disease or condition is
selected from pain mediated by the CNS, such as neuropathic pain,
inflammatory pain, and/or acute pain (for the use of certain
nucleoside and nucleotide compounds in treating these conditions,
see, for example, Br J Pharmacol. 2010 March; 159(5):1106-17. doi:
10.1111/j.1476-5381.2009.00596.x. Epub 2010 Feb. 5. "A comparative
analysis of the activity of ligands acting at P2X and P2Y receptor
subtypes in models of neuropathic, acute and inflammatory pain."
Ando RD1, Mehesz B, Gyires K, Illes P, Sperlagh B. PMID: 20136836),
hereby incorporated by reference).
In other embodiments, the disease or condition is selected from
cancer of the brain, such as glioblastoma (for the use of certain
nucleoside and nucleotide compounds in treating these conditions,
see, for example, Purinergic Signal. 2015 September; 11(3):331-46.
doi: 10.1007/s11302-015-9454-7. Epub 2015 May 15. "Potentiation of
temozolomide antitumor effect by purine receptor ligands able to
restrain the in vitro growth of human glioblastoma stem cells."
D'Alimonte, I. et al. PMID: 25976165, hereby incorporated by
reference). In other embodiments, the disease or condition is pain
(for the use of certain nucleoside and nucleotide compounds in
treating pain, see, for example, Pharmacol Biochem Behay. 2015
January; 128:23-32. doi: 10.1016/j.pbb.2014.11.001. Epub 2014 Nov.
6. "Participation of peripheral P2Y.sub.1, P2Y.sub.6 and P2Y.sub.11
receptors in formalin-induced inflammatory pain in rats."
Barragan-Iglesias P. et al. PMID: 25449358; and Neuropharmacology.
2014 April; 79:368-79. doi: 10.1016/j.neuropharm.2013.12.005. Epub
2013 Dec. 12. "Blockade of peripheral P2Y.sub.1 receptors prevents
the induction of thermal hyperalgesia via modulation of TRPV1
expression in carrageenan-induced inflammatory pain rats:
involvement of p38 MAPK phosphorylation in DRGs." Kwon S G, Roh D
H, Yoon S Y, Moon J Y, Choi S R, Choi H S, Kang S Y, Han H J, Beitz
A J, Lee J H. PMID: 24333674, each of which is hereby incorporated
by reference). In other embodiments, the disease or condition is
selected from a gastrointestinal disorder such as diarrhea (for the
use of certain nucleoside and nucleotide compounds in treating
these conditions, see, for example, Acta Physiol (Oxf). 2014
December; 212(4):293-305. doi: 10.1111/apha.12408. "Differential
functional role of purinergic and nitrergic inhibitory
cotransmitters in human colonic relaxation," Mane N., Gil V,
Martinez-Cutillas M, Clave P, Gallego D, Jimenez M., hereby
incorporated by reference). In other embodiments, the disease or
condition is impaired cognition (for the use of certain nucleoside
and nucleotide compounds in treating this condition, see, for
example, Neuropsychopharmacology. 2015 January; 40(2):305-14. doi:
10.1038/npp.2014.173. Epub 2014 Jul. 15. "Impaired cognition after
stimulation of P2Y.sub.1 receptors in the rat medial prefrontal
cortex," Koch H, Bespalov A, Drescher K, Franke H, Krugel U. PMID:
25027332, hereby incorporated by reference).
In some embodiments, the present invention provides a method of
treating a disease or condition associated with brain injury or a
neurodegenerative condition, such as epilepsy, migraine, collateral
brain damage associated with radiation cancer therapy, depression,
mood or behavioral changes, dementia, erratic behavior,
suicidality, tremors, Huntington's chorea, loss of coordination of
movement, deafness, impaired speech, dry eyes, hypomimia, attention
deficit, memory loss, cognitive difficulties, vertigo, dysarthria,
dysphagia, ocular abnormalities, or disorientation, comprising
administering to a patient in need thereof an effective amount of a
disclosed compound. In some embodiments, the compound is an
A.sub.3R agonist. In some embodiments, the compound is a P2Y.sub.1
agonist. In some embodiments, the compound is a biased agonist,
partial agonist, or biased partial agonist or antagonist at an
A.sub.3 receptor. In some embodiments, the compound acts by dual
agonism at an A.sub.3R and an A.sub.1R. In some embodiments, the
compound is a biased agonist, partial agonist, or biased partial
agonist or antagonist at a P2Y.sub.1 receptor. In some embodiments,
the compound is a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
In further embodiments, the present invention provides a method of
treating a neurodegenerative disease selected from the group
consisting of Alzheimer's disease, Parkinson's disease,
Huntington's disease, multiple sclerosis, amyotrophic lateral
sclerosis, and prion disease in a patient in need thereof,
comprising administering an effective amount of a disclosed
compound. In some embodiments, the compound is an A.sub.3R agonist.
In some embodiments, the compound is a P2Y.sub.1 agonist. In some
embodiments, the compound is a biased agonist, partial agonist, or
biased partial agonist or antagonist at an A.sub.3 receptor. In
some embodiments, the compound acts by dual agonism at an A.sub.3R
and an A.sub.1R. In some embodiments, the compound is a biased
agonist, partial agonist, or biased partial agonist or antagonist
at a P2Y.sub.1 receptor. In some embodiments, the compound is a
solid form of compound A, or a pharmaceutically acceptable
composition comprising the same.
In some embodiments, the improvement in cognitive or neurological
function is measured as a score increase between about 1% and 20%
in the delayed verbal recall task of the revised Wechsler Memory
Scale. For example, the improvement in cognitive function may be
measured as a score increase between about 1% and 10%, or between
about 1% and 5%.
In some embodiments, the present invention provides a method of
treating a brain or central nervous system (CNS) injury or
condition selected from traumatic brain injury (TBI) or stroke,
comprising administering to a patient in need thereof an effective
amount of a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
In some embodiments, the brain or central nervous system (CNS)
injury or condition is TBI. In some embodiments, the TBI is
selected from concussion, blast injury, combat-related injury, or a
mild, moderate or severe blow to the head.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is
administered within 24 hours of the TBI or stroke.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is
administered within 8 hours of the TBI or stroke.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is
administered at least during the first 8-48 hours following the TBI
or stroke.
In some embodiments, the brain or central nervous system (CNS)
injury or condition is stroke.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is
administered chronically to treat the stroke during the time period
after the stroke has occurred as it resolves.
In some embodiments, neuroprotection or neurorestoration is
increased in the patient as compared with an untreated patient.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is a
biased partial agonist at a human A.sub.3 adenosine receptor
(A.sub.3R). In some embodiments, the compound acts by dual agonism
at an A.sub.3R and an A.sub.1R.
In some embodiments, the A.sub.3R is partially agonized in a manner
biased toward neuroprotective functions of the A.sub.3R
receptor.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is
administered orally, intravenously, or parenterally.
In one aspect, the present invention provides a method of
increasing neuroprotection or neurorestoration in a patient who has
suffered a TBI or stroke, comprising administering to a patient in
need thereof an effective amount of a solid form of compound A, or
a pharmaceutically acceptable composition comprising the same.
In some embodiments, the neuroprotection or neurorestoration
decreases the recovery period after the TBI or stroke as compared
with an untreated patient.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is a
biased partial agonist at a human A.sub.3 adenosine receptor
(A.sub.3R) and the A.sub.3R is partially agonized in a manner
biased toward neuroprotective functions of the A.sub.3R receptor.
In some embodiments, the compound acts by dual agonism at an
A.sub.3R and an A.sub.1R.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is
administered orally, intravenously, or parenterally.
In one aspect, the present invention provides a method of treating
an injury, disease, or condition selected from traumatic brain
injury (TBI), stroke, a neurodegenerative condition, or a heart or
cardiovascular disease, comprising administering to a patient in
need thereof an effective amount of a solid form of compound A, or
a pharmaceutically acceptable composition comprising the same.
In some embodiments, the injury, disease, or condition is TBI. In
some embodiments, the TBI is selected from concussion, blast
injury, combat-related injury, or a mild, moderate or severe blow
to the head.
In some embodiments, the injury, disease, or condition is a stroke
selected from ischemic stroke, hemorrhagic stroke, subarachnoid
hemorrhage, cerebral vasospasm, or transient ischemic attacks
(TIA).
In some embodiments, the neurodegenerative disease is selected from
Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's
Disease (HD), Multiple Sclerosis (MS), amyotrophic lateral
sclerosis (ALS), chronic traumatic encephalopathy (CTE), or a
neurodegenerative condition caused by a virus, alcoholism, tumor,
toxin, or repetitive brain injuries.
In some embodiments, the injury, disease, or condition is
Parkinson's Disease.
In some embodiments, the injury, disease, or condition is
Alzheimer's Disease, migraine, brain surgery, or a neurological
side effect associated with cancer chemotherapy.
In some embodiments, the heart or cardiovascular disease is
selected from cardiac ischemia, myocardial infarction, a
cardiomyopathy, coronary artery disease, arrhythmia, myocarditis,
pericarditis, angina, hypertensive heart disease, endocarditis,
rheumatic heart disease, congenital heart disease, or
atherosclerosis.
In some embodiments, the heart or cardiovascular disease is cardiac
ischemia or myocardial infarction.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is
administered chronically to treat the stroke, cardiac ischemia, or
myocardial infarction during the time period after the injury has
occurred as it resolves.
In some embodiments, neuroprotection or neurorestoration is
increased in the patient as compared with an untreated patient.
In some embodiments, the A.sub.3R is agonized in a biased manner
toward neuroprotective functions of the A.sub.3R receptor via
preferential activation of intracellular calcium mobilization with
less, or no, activation of other A.sub.3R-mediated pathways, or via
preferential activation of Gq11-mediated intracellular calcium
mobilization, Gi-mediated modulation of cAMP production, or
Gi-mediated phosphorylation of ERK1/2 and Akt.
In some embodiments, the A.sub.3R is partially agonized in a manner
biased toward cardioprotective functions of the A.sub.3R receptor
via preferential activation of intracellular calcium mobilization
with less, or no, activation of other A.sub.3R-mediated pathways,
or via preferential activation of Gq11-mediated intracellular
calcium mobilization, Gi-mediated modulation of cAMP production, or
Gi-mediated phosphorylation of ERK1/2 and Akt.
In some embodiments, the method increases neuroprotection or
neurorestoration in a patient who is suffering from a neurological
side effect associated with or resulting from cancer chemotherapy
or brain surgery.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is
administered orally.
In one aspect, the present invention provides a method of
increasing neuroprotection or neurorestoration in a patient who has
suffered a TBI or stroke, thereby treating the TBI or stroke,
comprising administering to a patient in need thereof an effective
amount of a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
In one aspect, the present invention provides a method of
increasing cardioprotection or regeneration of damaged heart tissue
in a patient who has suffered a cardiac ischemia or myocardial
infarction, thereby treating the cardiac ischemia or myocardial
infarction, comprising administering to a patient in need thereof
an effective amount of a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same.
In some embodiments, the recovery period after the TBI, stroke,
cardiac ischemia, or myocardial infarction is decreased as compared
with an untreated patient.
In some embodiments, the A.sub.3R is partially agonized in a manner
biased toward neuroprotective functions of the A.sub.3R
receptor.
In some embodiments, the A.sub.3R is partially agonized in a manner
biased toward cardioprotective functions of the A.sub.3R
receptor.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is
administered orally.
In some embodiments, the compound is a biased agonist of an
A.sub.3R with improved cardioprotection function relative to a full
A.sub.3R agonist.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is a
biased agonist of an A.sub.3R with improved cardioprotection
function relative to a full A.sub.3R agonist via preferential
activation of one or more of the following A.sub.3R-mediated
pathways: activation of Gq11-mediated intracellular calcium
mobilization, Gi-mediated modulation of cAMP production,
Gi-mediated phosphorylation of ERK1/2 and Akt, or modulation of
Beta-Arrestin activation.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is a
biased agonist of an A.sub.3R with improved cardioprotection
function relative to a full A.sub.3R agonist via preferential
activation of intracellular calcium mobilization with less or no
activation of the other A.sub.3R-mediated pathways.
In some embodiments, a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same, is a
partial agonist of the A.sub.3R with improved cardioprotection
function relative to a full A.sub.3R agonist.
Addictive Disorders
Disclosed compounds are also useful in treating addictions,
addictive behaviors, behavioral addictions, compulsive disorders
and behaviors, and related conditions.
The use of compounds such as compound A in treating such
addictions, behaviors, and disorders is described in
WO/2019/157317, the contents of which are hereby incorporated by
reference.
Cocaine self-administering mice exhibit significantly higher
glutamate levels in the VTA (ventral tegmental area) of the brain.
The VTA, in particular the VTA dopamine neurons, serve several
functions in the reward system, motivation, cognition, and drug
addiction, and may be the focus of several psychiatric disorders.
The elevated glutamate levels appear to be due, at least in part,
to loss of glutamate uptake into astrocytes. Without wishing to be
bound by theory, it is believed that reduced availability of
glutamate has negative effects on astrocyte function and this loss
of function affects neuronal activity and drug-seeking behavior. It
has now been found that the compounds disclosed herein treat or
prevent relapse in addicted individuals, for example by reversing
such loss of astrocyte function. Such loss of astrocyte function
may be partly due to reduced expression of the glutamate
transporter (GLT-1) in astrocytes. Since astrocytes metabolize
glutamate to produce ATP, this likely impairs glutamate uptake,
weakens astrocyte oxidative metabolism and downstream ATP-dependent
processes and thereby weakens their ability to maintain an optimal
environment for VTA neuronal activity.
Accordingly, in one aspect, the present invention provides a method
of preventing, ameliorating, treating, or promoting recovery from
an addiction, addictive behavior, behavioral addiction, brain
reward system disorder, compulsive disorder, or related condition,
comprising administering to a subject in need thereof an effective
amount of a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
In some embodiments, the addiction is to an addictive substance. In
some embodiments, the addictive substance is a prescription or
recreational drug.
In some embodiments, the addictive substance is selected from
alcohol, nicotine, a stimulant, a cannabinoid agonist, or an opioid
agonist. In some embodiments, the addictive substance is selected
from heroin, cocaine, alcohol, an inhalant, an opioid, nicotine, an
amphetamine, or a synthetic analog, salt, composition, or
combination thereof.
In some embodiments, the amphetamine is selected from bupropion,
cathinone, MDMA, or methamphetamine.
In some embodiments, the prescription or recreational drug is
selected from a cannabinoid agonist or opioid agonist.
In some embodiments, the addiction is an alcohol or nicotine
addiction.
In some embodiments, the subject is a polydrug abuser.
In some embodiments, the prescription or recreational drug is
selected from cocaine, heroin, bupropion, cathinone, MDMA, or
methamphetamine morphine, oxycodone, hydromorphone, fentanyl, or a
combination thereof.
In some embodiments, a disclosed compound increases energy
metabolism mediated by astrocytes, such as astrocyte mitochondria.
In some embodiments, the compound reverses loss of glutamate uptake
into astrocytes caused by a substance with abuse potential. In some
embodiments, the compound at least partially reverses the
remodeling of the brain reward system caused by the addiction. In
some embodiments, such effects are mediated by brain or CNS
adenosine A.sub.3 receptors, such as astrocyte A.sub.3R in the VTA;
or microglia A.sub.3R.
In another aspect, the present invention provides a method of
preventing, ameliorating, treating, or promoting recovery from an
addiction, addictive behavior, behavioral addiction brain reward
system disorder, compulsive disorder, or related condition by
increasing energy metabolism mediated by astrocytes, glia,
microglia, neurons, endothelium cells, or other cells of the brain
and/or CNS, comprising administering to a subject in need thereof
an effective amount of a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same.
In some embodiments, the method treats or prevents a relapse of an
addiction or addictive behavior in the subject. In some
embodiments, the subject is addicted to one or more addictive
substances such as addictive drugs (drugs having abuse potential).
As described below, such drugs include prescription drugs and
recreational drugs such as heroin, cocaine, nicotine, or an opioid
agonist.
In another aspect, the present invention provides a method of
treating or preventing withdrawal caused by addiction to one or
more addictive substances or drugs, comprising administering to a
subject in need thereof an effective amount of a solid form of
compound A, or a pharmaceutically acceptable composition comprising
the same. In some embodiments, the compound decreases withdrawal
symptoms in an addicted individual in withdrawal. In some
embodiments, the compound treats withdrawal in an addicted
individual in withdrawal. In some embodiments, the method further
comprises co-administering another drug for treating withdrawal
and, optionally, counseling such as psychotherapy. In some
embodiments, the method further comprises a cognitive behavioral
therapy. In some embodiments, the method further comprises a
digital therapeutic. Digital therapeutics include, for example,
reSET or reSET-O (Pear Therapeutics).
In some embodiments, the present invention provides a method of
treating or preventing a relapse of a compulsive disorder or
compulsive behavior, comprising administering to a subject in need
thereof an effective amount of a solid form of compound A, or a
pharmaceutically acceptable composition comprising the same.
In some embodiments, the compulsive disorder is
obsessive-compulsive disorder (OCD), Tourette syndrome,
trichotillomania, anorexia, bulimia, anxiety disorder, psychosis,
or post-traumatic stress disorder.
According to another aspect, the present invention provides a
method for treating one or more behavioral addictions and addictive
behaviors or disorders comprising administering to a subject in
need thereof a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same. Behavioral addictions
and addictive disorders result from the intoxication one senses
from the release of brain chemicals (e.g., serotonin, adrenaline,
epinephrine, etc.) during certain activities. Such disorders are
known in the art and include gambling, sex addiction, pornography
addiction, eating disorders, spending addiction, rage/anger,
workaholism, exercise addiction, risk taking addictions (e.g.
kleptomania and pyromania), perfectionism, internet or video game
addiction, and compulsive use of electronic devices such as texting
and checking social media, to name a few.
In some embodiments, activation of astrocytes is achieved through
contacting with a disclosed compound one or more purinergic
receptors such as adenosine receptors (ARs), for example those
associated with or expressed by astrocytes or microglia, thus
modulating the activity of the one or more receptors. In some
embodiments, through effects on adenosine receptors such as
A.sub.1, A.sub.2A, A.sub.2B and A.sub.3 on astrocytes, the compound
activates astrocytes to treat one or more disclosed diseases or
conditions. In some embodiments, after administration to a subject
in need thereof, a disclosed compound influences one or more
functions such as glutamate uptake having an impact on energy
metabolism of astrocytes or neuronal function, thus treating one or
more diseases or conditions. In some embodiments, the compound is
an AR agonist. In some embodiments, the purinergic receptor is an
adenosine A.sub.3 receptor (A.sub.3R). In some embodiments, the
compound is an A.sub.3R agonist. In some embodiments, the compound
is a partial agonist or biased agonist or biased partial agonist,
at an A.sub.3 receptor (A.sub.3R), such as a human A.sub.3 receptor
(hA3R). In some embodiments, the compound is a biased antagonist at
an A.sub.3 receptor. In some embodiments, the compound acts by dual
agonism at an A.sub.3R and an A.sub.1R. In some embodiments, the
compound is a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
P2Y receptors are G-protein-coupled receptors and different
subtypes of these receptors have important roles in processes such
as synaptic communication, cellular differentiation, ion flux,
vasodilation, blood brain barrier permeability, platelet
aggregation and neuromodulation. Characterized members of the
purinergic P2Y receptor family include the mammalian P2Y.sub.1,
P2Y.sub.11, P2Y.sub.12 and P2Y.sub.13 receptors, which bind to
adenine nucleotides; the P2Y.sub.4, P2Y.sub.6, and P2Y.sub.14
receptors, that bind to uracil nucleotides; and the P2Y.sub.2 and
rodent P2Y.sub.4 receptors, which have mixed selectivity. In some
embodiments, activation of astrocytes is achieved through
contacting with a disclosed compound one or more purinergic
receptors such as P2Y receptors, for example those associated with
or expressed by astrocytes, thus modulating the activity of the one
or more receptors. In some embodiments, through effects on P2Y
receptors such as P2Y.sub.1, P2Y.sub.11, P2Y.sub.12 and P2Y.sub.13
receptors associated with or expressed by astrocytes, the compound
activates astrocytes to treat one or more disclosed diseases or
conditions. In some embodiments, the P2Y receptor is a P2Y.sub.1
receptor. In some embodiments, the P2Y.sub.1 receptor is located on
intracellular mitochondrial membranes. In some embodiments, the
compound is a P2Y agonist. In some embodiments, the compound is a
P2Y.sub.1 agonist, e.g. at a human P2Y.sub.1 receptor. In some
embodiments, the compound is a biased agonist, partial agonist, or
biased partial agonist at a P2Y.sub.1 receptor, such as a human
P2Y.sub.1 receptor. In some embodiments, the compound is a biased
antagonist at a P2Y.sub.1 receptor. In some embodiments, the
compound is a solid form of compound A, or a pharmaceutically
acceptable composition comprising the same.
As used herein, the term "addiction" includes, unless otherwise
specified, physical or psychological dependence on a substance.
Addiction may involve withdrawal symptoms or mental or physical
distress if the substance is withdrawn. Addiction includes drug
liking, drug dependence, habit-formation, neurological and/or
synaptic changes, development of brain reward system disorders,
behavioral changes, or other signs or symptoms of addiction in a
subject.
As used herein, the term "addictive drug" or "drug having abuse
potential" includes drugs and other substances such as nicotine,
whether approved by a regulatory body for treatment of a disease or
not, that are known to result in clinical, behavioral, or
neurological manifestations of addiction or compulsive behavior. In
some embodiments, the addictive drug includes nicotine, a
cannabinoid agonist, a stimulant, or an opioid agonist. "Addictive
substance" refers to addictive drugs as well as other substances of
abuse such as alcohol. Examples of addictive substances thus
include heroin, cocaine, alcohol, opiates, nicotine, inhalants,
amphetamines, and their synthetic analogs.
Pharmaceutically Acceptable Compositions
According to another embodiment, the invention provides a
composition comprising a disclosed compound and a pharmaceutically
acceptable carrier, adjuvant, or vehicle. In certain embodiments, a
composition of this invention is formulated for administration to a
patient in need of such composition. In some embodiments, a
composition of this invention is formulated for oral administration
to a patient.
The term "biological sample," as used herein, includes, without
limitation, cell cultures or extracts thereof; biopsied material
obtained from a mammal or extracts thereof; and blood, saliva,
urine, feces, semen, tears, or other body fluids or extracts
thereof.
The term "patient," as used herein, means an animal, preferably a
mammal, and most preferably a human.
The term "pharmaceutically acceptable carrier, adjuvant, or
vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that
does not destroy the pharmacological activity of the compound with
which it is formulated. Pharmaceutically acceptable carriers,
adjuvants or vehicles that may be used in the compositions of this
invention include, but are not limited to, ion exchangers, alumina,
aluminum stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
A "pharmaceutically acceptable derivative" means any non-toxic
salt, ester, salt of an ester or other derivative of a compound of
this invention that, upon administration to a recipient, is capable
of providing, either directly or indirectly, a compound of this
invention or an inhibitorily active metabolite or residue
thereof.
The compounds and compositions, according to the method of the
present invention, are administered using any amount and any route
of administration effective for treating or lessening the severity
of a disorder provided above. The exact amount required will vary
from subject to subject, depending on the species, age, and general
condition of the subject, the severity of the infection, the
particular agent, its mode of administration, and the like.
Compounds of the invention are preferably formulated in dosage unit
form for ease of administration and uniformity of dosage. The
expression "dosage unit form" as used herein refers to a physically
discrete unit of agent appropriate for the patient to be treated.
It will be understood, however, that the total daily usage of the
compounds and compositions of the present invention will be decided
by the attending physician within the scope of sound medical
judgment. The specific effective dose level for any particular
patient or organism will depend upon a variety of factors including
the disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed, and like
factors well known in the medical arts.
Pharmaceutically acceptable compositions of this invention can be
administered to humans and other animals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), buccally, as an
oral or nasal spray, or the like, depending on the severity of the
infection being treated. In certain embodiments, the compounds of
the invention are administered orally or parenterally at dosage
levels of about 0.01 mg/kg to about 50 mg/kg and preferably from
about 0.01 mg/kg to about 25 mg/kg, of subject body weight per day,
one or more times a day, to obtain the desired therapeutic effect.
In certain embodiments, the compounds of the invention are
administered orally or parenterally at dosage levels of about 0.01
mg/kg to about 50 mg/kg, or about 0.01 mg/kg to about 25 mg/kg, or
about 0.05 mg/kg to about 10 mg/kg, or about 0.05 mg/kg to about 5
mg/kg, or about 0.1 mg/kg to about 2.5 mg/kg, of subject body
weight per day, one or more times a day, to obtain the desired
therapeutic effect.
Liquid dosage forms for oral administration include, but are not
limited to, pharmaceutically acceptable emulsions, liposomes,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or
oleaginous suspensions may be formulated according to the known art
using suitable dispersing or wetting agents and suspending agents.
The sterile injectable preparation may also be a sterile injectable
solution, suspension or emulsion in a nontoxic parenterally
acceptable diluent or solvent, for example, as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, U.S.P. and isotonic
sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
are used in the preparation of injectables.
Injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters), poly(anhydrides)
and cyclodextrins and modified cyclodextrins (such as SBE-bCD).
Depot injectable formulations are also prepared by entrapping the
compound in liposomes or microemulsions that are compatible with
body tissues.
Compositions for rectal or vaginal administration are preferably
suppositories which can be prepared by mixing the compounds of this
invention with suitable non-irritating excipients or carriers such
as cocoa butter, polyethylene glycol or a suppository wax which are
solid at ambient temperature but liquid at body temperature and
therefore melt in the rectum or vaginal cavity and release the
active compound.
Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polyethylene
glycols and the like.
The active compounds can also be in micro-encapsulated form with
one or more excipients as noted above. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
The compounds of the invention can also be administered topically,
such as directly to the eye, e.g., as an eye-drop or ophthalmic
ointment. Eye drops typically comprise an effective amount of at
least one compound of the invention and a carrier capable of being
safely applied to an eye. For example, the eye drops are in the
form of an isotonic solution, and the pH of the solution is
adjusted so that there is no irritation of the eye. In many
instances, the epithelial barrier interferes with penetration of
molecules into the eye. Thus, most currently used ophthalmic drugs
are supplemented with some form of penetration enhancer. These
penetration enhancers work by loosening the tight junctions of the
most superior epithelial cells (Burstein, 1985, Trans Ophthalmol
Soc U K 104(Pt 4): 402-9; Ashton et al., 1991, J Pharmacol Exp Ther
259(2): 719-24; Green et al., 1971, Am J Ophthalmol 72(5):
897-905). The most commonly used penetration enhancer is
benzalkonium chloride (Tang et al., 1994, J Pharm Sci 83(1): 85-90;
Burstein et al, 1980, Invest Ophthalmol Vis Sci 19(3): 308-13),
which also works as preservative against microbial contamination.
It is typically added to a final concentration of 0.01-0.05%.
Combinations with Other Therapeutic Agents
Depending upon the particular condition, or disease, to be treated,
additional therapeutic agents that are normally administered to
treat that condition, may also be present in the compositions of
this invention. As used herein, additional therapeutic agents that
are normally administered to treat a particular disease, or
condition, are known as "appropriate for the disease, or condition,
being treated."
In certain embodiments, a provided compound, or composition
thereof, is administered in combination with other therapeutic
agents, such as tissue plasminogen activators, blood thinners,
statins, ACE inhibitors, angiotensin II receptor blockers (ARBs),
beta blockers, calcium channel blockers or diuretics, to a patient
in need thereof.
In certain embodiments, the tissue plasminogen activator used in
combination with compounds or compositions of the invention
include, but are not limited to, alteplase, desmoteplase,
reteplase, tenecteplase, or combinations of any of the above.
In certain embodiments, the blood thinners used in combination with
compounds or compositions of the invention include, but are not
limited to, warfarin, heparin, apixabam, clopidogrel, aspirin,
rivaroxaban, dabigatran, or combinations of any of the above.
In certain embodiments, the statins used in combination with
compounds or compositions of the invention include, but are not
limited to, atorvastatin, rosuvastatin, fluvastatin, lovastatin,
pravastatin, simvastatin and pitavastatin, cerivastatin,
mevastatin, or combinations of any of the above.
In certain embodiments, the ACE inhibitors used in combination with
compounds or compositions of the invention include, but are not
limited to, captopril, enalapril, fosinopril, lisinopril,
moexipril, perindopril, quinapril, ramipril, trandolapril
benazepril, or combinations of any of the above.
In certain embodiments, the angiotensin II receptor blockers (ARBs)
used in combination with compounds or compositions of the invention
include, but are not limited to, azilsartan, candesartan,
eprosartan, irbesartan, losartan, olmesartan, telmisartan,
valsartan, fimasartan, or combinations of any of the above.
In certain embodiments, the beta blockers used in combination with
compounds or compositions of the invention include, but are not
limited to, atenolol, bisoprolol, betaxolol, carteolol, carvedilol,
labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol,
pindolol, propranolol, timolol, or combinations of any of the
above.
In certain embodiments, the calcium channel blockers used in
combination with compounds or compositions of the invention
include, but are not limited to, dihydropyridines: amlodipine,
cilnidipine, clevidipine, felodipine, isradipine, lercanidipine,
levamlodipine, nicardipine, nifedipine, nimodipine, nisoldipine,
nitrendipine, diltiazem, verapamil, or combinations of any of the
above.
In certain embodiments, the diuretics used in combination with
compounds or compositions of the invention include, but are not
limited to, loop diuretics, thiazide diuretics, thiazide-like
diuretics and potassium-sparing diuretics, or combinations of any
of the above.
In certain embodiments, the loop diuretics used in combination with
compounds or compositions of the invention include, but are not
limited to, bumetanide, ethacrynic acid, furosemide, torsemide, or
combinations of any of the above.
In certain embodiments, the thiazide diuretics used in combination
with compounds or compositions of the invention include, but are
not limited to, epitizide, hydrochlorothiazide and chlorothiazide,
bendroflumethiazide, methyclothiazide, polythiazide, or
combinations of any of the above.
In certain embodiments, the thiazide-like diuretics used in
combination with compounds or compositions of the invention
include, but are not limited to, indapamide, chlorthalidone,
metolazone, or combinations of any of the above.
In certain embodiments, the potassium-sparing diuretics used in
combination with compounds or compositions of the invention
include, but are not limited to, amiloride, triamterene,
spironolactone, eplerenone, or combinations of any of the
above.
In certain embodiments, a provided compound, or composition
thereof, is administered in combination with a mechanical
thrombectomy device, to a patient in need thereof. In certain
embodiments, the mechanical thrombectomy device is a stroke
thrombectomy device or a coil embolization device for cerebral
aneurysm. In certain embodiments, such a device includes, but is
not limited to, a coil retriever, an aspiration device or a stent
retriever.
In certain embodiments, a combination of 2 or more therapeutic
agents may be administered together with compounds or compositions
of the invention. In certain embodiments, a combination of 3 or
more therapeutic agents may be administered together with compounds
or compositions of the invention.
Those additional agents may be administered separately from an
inventive compound-containing composition, as part of a multiple
dosage regimen. Alternatively, those agents may be part of a single
dosage form, mixed together with a compound of this invention in a
single composition. If administered as part of a multiple dosage
regime, the two active agents may be submitted simultaneously,
sequentially or within a period of time from one another, normally
within five hours from one another.
As used herein, the term "combination," "combined," and related
terms refers to the simultaneous or sequential administration of
therapeutic agents in accordance with this invention. For example,
a compound of the present invention may be administered with
another therapeutic agent simultaneously or sequentially in
separate unit dosage forms or together in a single unit dosage
form. Accordingly, the present invention provides a single unit
dosage form comprising a compound of the present invention, an
additional therapeutic agent, and a pharmaceutically acceptable
carrier, adjuvant, or vehicle.
The amount of both, a provided compound and additional therapeutic
agent (in those compositions which comprise an additional
therapeutic agent as described above) that may be combined with the
carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. Preferably, compositions of this invention should
be formulated so that a dosage of between 0.01-100 mg/kg body
weight/day of an inventive compound can be administered.
In those compositions which comprise an additional therapeutic
agent, that additional therapeutic agent and the compound of this
invention may act synergistically. Therefore, the amount of
additional therapeutic agent in such compositions will be less than
that required in a monotherapy utilizing only that therapeutic
agent. In such compositions a dosage of between about 0.001-100
mg/kg body weight/day of the additional therapeutic agent can be
administered, or about 0.001 mg/kg to about 500 .mu.g/kg, or about
0.005 mg/kg to about 250 .mu.g/kg, or about 0.01 mg/kg to about 100
.mu.g/kg body weight/day of the additional therapeutic agent can be
administered.
The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
In one embodiment, the present invention provides a composition
comprising a compound of the present invention and one or more
additional therapeutic agents. The therapeutic agent may be
administered together with a compound of the present invention, or
may be administered prior to or following administration of a
compound of the present invention. Suitable therapeutic agents are
described in further detail below. In certain embodiments, a
compound of the present invention may be administered up to 5
minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3
hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10
hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours,
17 hours, or 18 hours before the therapeutic agent. In other
embodiments, a compound of the present invention may be
administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1
hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8
hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours,
15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic
agent.
In some embodiments, the present invention provides a medicament
comprising at least one compound of the present invention or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
All features of each of the aspects of the invention apply to all
other aspects mutatis mutandis.
In order that the invention described herein may be more fully
understood, the following examples are set forth. It should be
understood that these examples are for illustrative purposes only
and are not to be construed as limiting this invention in any
manner.
EXEMPLIFICATION
As depicted in the Examples below, in certain exemplary
embodiments, compounds are prepared according to the following
general procedures. It will be appreciated that, although the
general methods depict the synthesis of certain compounds of the
present invention, the following general methods, and other methods
known to one of ordinary skill in the art, can be applied to all
compounds and subclasses and species of each of these compounds, as
described herein.
General Procedures
X-ray powder diffraction (XRPD) analysis was carried out on a
Rigaku Smart-Lab X-ray diffraction system. The Rigaku Smart-Lab
X-ray diffraction system was configured for reflection
Bragg-Brentano geometry using a line source X-ray beam. The x-ray
source is a Cu Long Fine Focus tube that was operated at 40 kV and
44 ma. That source provides an incident beam profile at the sample
that changes from a narrow line at high angles to a broad rectangle
at low angles. Beam conditioning slits are used on the line X-ray
source to ensure that the maximum beam size is less than 10 mm both
along the line and normal to the line. The Bragg-Brentano geometry
is a para-focusing geometry controlled by passive divergence and
receiving slits with the sample itself acting as the focusing
component for the optics. The inherent resolution of Bragg-Brentano
geometry is governed in part by the diffractometer radius and the
width of the receiving slit used. Typically, the Rigaku Smart-Lab
is operated to give peak widths of 0.1.degree.2.theta. or less. The
axial divergence of the X-ray beam is controlled by 5.0-degree
Soller slits in both the incident and diffracted beam paths. The
instrument is qualified using ASTM silicon standard on the same day
of the analysis.
Powder samples were prepared in a low background Si holder using
light manual pressure to keep the sample surfaces flat and level
with the reference surface of the sample holder. Each sample was
analyzed from 2 to 40.degree.2.theta. using a continuous scan of
6.degree.2.theta. per minute with an effective step size of
0.02.degree.2.theta..
Thermogravimetric Analysis (TGA) was carried out using a TA
Instruments Q50 instrument. The instrument balance was calibrated
using class M weights and the temperature calibration was performed
using alumel. The nitrogen purge was .about.40 mL per minute at the
balance and .about.60 mL per minute at the furnace. Each sample
(about 2-5 mg) was placed into a pre-tared platinum pan and heated
from 20.degree. C. to 350.degree. C. at a rate of 10.degree. C. per
minute. The heating rate can impact the outcome of the analysis
results. Nitrogen purge rate can be varied as appropriate for the
specific instrument specifications.
Differential Scanning calorimetry (DSC) analyses were carried out
using a TA Instruments Q2000 instrument. The instrument temperature
calibration was performed using indium. The DSC cell was kept under
a nitrogen purge of .about.50 mL per minute during each analysis.
The sample (about 1-2 mg) was placed in a standard, crimped,
aluminum pan and was heated from 25.degree. C. to 350.degree. C. at
a rate of 10.degree. C. per minute. The type of pan, preparation of
the pan for analysis, and heating rate can impact the outcome of
the analysis results. Nitrogen purge rate can be varied as
appropriate for the specific instrument specifications.
Dynamic Vapour Sorption (DVS) analysis was carried out using a TA
Instruments Q5000 Dynamic Vapor Sorption analyzer. The instrument
was calibrated with standard weights and a sodium bromide standard
for humidity. Approximately 20 mg of sample was loaded into a
metal-coated quartz pan for analysis. The sample was analyzed at
25.degree. C. with a maximum equilibration time of one hour in 10%
relative humidity (RH) steps from 5 to 95% RH (adsorption cycle)
and from 95 to 5% RH (desorption cycle). The movement from one step
to the next occurred either after satisfying the equilibrium
criterion of 0.01% weight change or, if the equilibrium criterion
was not met, after one hour. The percent weight change values were
calculated using Microsoft Excel.RTM.. The temperature for the DVS
analysis can impact the outcome of the results.
Karl Fischer (KF) analysis were carried out using a Mettler-Toledo
C20 Coulometric KF titrator. The instrument was calibrated using a
Hydranal water standard containing 1% water. The titrant was a
Hydranal methanol solution. The sample was analyzed in
triplicate.
Optical Microscopy (OM) analysis were carried out on a Leica DM
2500 P compound microscope with a 10.times. magnification eye piece
and a 10.times. magnification objective, for a total magnification
of 100.times.. Images were captured using a Qlmaging MicroPublisher
3.3 RTV camera. The polarizing microscopy image (in color) was
obtained with the sample in mineral oil, with transmitted light
from the microscope and polarizers in place.
Infrared (IR) Spectra were obtained using a Thermo Nicolet model
6700 Fourier-transform (FT) IR spectrophotometer equipped with a
deuterated triglycine sulfate (DTGS) detector, a potassium bromide
(KBr) beamsplitter, and an electronically temperature controlled
(ETC) Ever-Gb.RTM. IR source. The instrument was configured with a
SMART iTR diamond attenuated total reflectance (ATR) sampling
accessory. The single beam scan of the background (air) and sample
were collected with 128 signal-averaged scans at a resolution of 2
cm.sup.-1 over the spectral range 4000-400 cm.sup.-1. The final
sample spectrum was automatically calculated and presented in Log
1/R units. The wavelength calibration was verified using a
certified polystyrene standard. Data collection and processing was
performed using Omnic 9.7.46 software.
FT-Raman Spectra were acquired on a Nicolet model 6700 spectrometer
interfaced to a Nexus Raman accessory module. This instrument is
configured with a Nd:YAG laser operating at 1024 nm, a CaF.sub.2
beamsplitter, and a indium gallium arsenide detector. Samples were
packed into a 3-inch glass NMR tube for analysis. The FT-Raman
spectrum was collected with 256 signal-averaged scans at a
resolution of 4 cm.sup.-1 over the spectral range 3700-100
cm.sup.-1. Data collection and processing was performed using Omnic
9.7.46 software.
.sup.13C Nuclear Magnetic Resonance (NMR) Spectra were obtained by
solid-state .sup.13C cross polarization magic angle spinning
(CPMAS) experiments were carried out on a 363 MHz Tecmag-based
spectrometer. Each sample (approximately 200 mg) was packed into a
7-mm zirconia rotor closed with kel-F end caps for subsequent data
acquisition. Glycine, set to 176.0 ppm, was used as an external
standard. Acquisition and processing parameters used are shown in
Table 3 below.
TABLE-US-00003 TABLE 3 Acquisition and Processing Parameters for
.sup.13C NMR. Nucleus .sup.13C Temperature (K) 293 Observe
Frequency (MHz) 91.37 Sweep Width (Hz) 29762 Dwell Time (.mu.sec)
33.6 1H pulse (.mu.sec) 5 CP time (msec) 1 Hartmann-Hahn contact 1
time (msec) Pulse width (.mu.sec) 1000 Acquisition Time (msec) 34
Recycle Delay (sec) 20 Spin Speed (kHz) 7.0 Number of Scans 176
Processing Parameters Reference external Line Broadening (Hz)
15
Milling was performed using a Retsch Mill. About 20 mg of material
was placed into a plastic grinding cup followed by 10 .mu.L of
water and a stainless-steel ball. The sample was then milled at
100% power for 20 minutes.
Example A--General Preparation of Compound A
##STR00004##
The title compound was prepared according to the steps and
intermediates (e.g., Scheme 1 and Scheme 2) described below and in
the '131 patent and '363 publication, the entireties of each of
which is incorporated herein by reference.
##STR00005## ##STR00006##
Zhan cat-1B has the following structure:
##STR00007##
Scheme 2 shows the remainder of the synthesis.
##STR00008##
Example 1--Preparation of Free Base Form A of Compound A
##STR00009##
Compound A is prepared according to the methods described in detail
in Example 9 of the '131 patent and '363 publication, the
entireties of each of which is incorporated herein by reference.
Scheme 3 below provides details of the synthesis of Compound A. An
intermediate of the synthesis shown in Scheme 3 was used to prepare
Form A of Compound A.
##STR00010## ##STR00011## ##STR00012## Form A of Compound A
Form A of compound A was prepared as described below.
Form A of Compound A--Preparation Method 1
Compound 13 of Scheme 3 (350 g, 0.58 mol) and water (2 L) was added
to a 3 L round bottom flask. 200 mL of trifluoroacetic acid (TFA)
was added and the mixture was stirred at 60.degree. C. for 12 hrs.
HPLC showed the reaction was complete. The mixture was cooled to
room temperature and washed with by methylene chloride (MC, 300
mL*3) and concentrated. The basic resin Amberlyst 21 was added to
the mixture to achieve a pH of about 9 and the mixtures was stirred
for 16 hours at room temperature. The mixture was then filtered,
washed with methanol (MeOH) and concentrated. Purification by
column chromatography was carried out [SiO.sub.2(5 X), MC/MeOH=15/1
to 5/1 (100 V)) to yield Compound A as light yellow solid. Compound
A was then dissolved in HPLC-grade MeOH to a clear solution and
rotary evaporated (water pump, bath temperature 35.degree. C.).
Form A of compound A was formed gradually during the concentration.
After most of the MeOH was removed (no weight change), deionized
water was added and rotary evaporated to dryness three times (oil
pump, bath temperature 35.degree. C.) to remove residual MeOH. The
obtained compound was further dried by rotary evaporation (oil
pump, bath temperature 35.degree. C.) until no weight change
(.about.16 hours), yielding Form A of compound A.
Form A of Compound A--Preparation Method 2
To a plastic grinding cup was added 18.4 mg of Compound A and 10
.mu.L of water. A stainless-steel ball was added. The sample was
then milled on a Retsch mill at 100% power for 20 minutes at room
temperature.
Form A of Compound A--Preparation Method 3
To a 20 mL glass vial was added 200.0 mg of Compound A and 3.0 mL
of water. A magnetic stir bar was added and the vial was capped.
The vial was placed on a heating/stirring plate and the slurry was
stirred magnetically for 7 days at ambient temperature. The vial
was centrifuged for 10 minutes and the mother liquor was decanted.
A dry air purge was directed into the vial for 10 minutes to dry
the solid. The vial was then placed in a room temperature vacuum
desiccator for 2 hours.
Form A of Compound A--Preparation Method 4
To a 20 mL glass vial was added 200.0 mg of Compound A and 3.0 mL
of water. A magnetic stir bar was added and the vial was capped.
The vial was placed on a heating/stirring plate set at 60.degree.
C. and the slurry was stirred magnetically for 3 days. The vial was
centrifuged for 10 minutes and the mother liquor was decanted. A
dry air purge was directed into the vial for 10 minutes to dry the
solid. The vial was then placed in a room temperature vacuum
desiccator for 2 hours.
Table 1, supra, is reproduced below and sets forth the X-ray
diffraction peaks observed for Form A of compound A.
TABLE-US-00004 TABLE 1 XRPD Peak Positions for Form A of Compound
A. Relative Relative Relative .degree.2.theta. Intensity
.degree.2.theta. Intensity .degree.2.theta. In- tensity 7.6 1.49
21.5 35.63 30.8 12.79 8.0 100 22.8 2.30 32.0 8.32 9.0 3.49 23.1
6.16 32.8 8.27 10.8 4.60 23.7 4.21 32.9 13.11 11.8 1.59 23.9 9.39
33.7 9.73 12.5 4.59 24.9 54.39 34.7 4.31 13.1 59.02 26.1 32.89 36.3
3.98 16.2 34.56 26.5 13.26 36.7 8.82 16.7 37.68 26.6 22.22 37.9
12.68 17.2 10.65 27.1 60.62 38.2 3.16 17.9 45.59 28.6 10.52 38.5
1.75 18.1 16.05 29.3 1.66 38.7 2.83 18.3 10.91 29.7 9.05 39.6 2.37
19.8 4.96 30.1 1.89 -- -- 21.0 30.62 30.4 1.77 -- --
Table 4, shown below, sets forth the FT-IR peaks observed for Form
A of compound A.
TABLE-US-00005 TABLE 4 FT-IR peak listing for Form A of compound A.
Wavenumbers (cm .sup.-1) 3460 1329 870 3293 1310 828 3178 1245 786
3114 1227 742 3008 1199 680 2921 1129 636 2887 1089 560 2871 1072
545 1629 1054 523 1580 1041 477 1510 1020 450 1457 975 418 1423 945
-- 1406 886 --
Table 5, shown below, sets forth the FT-Raman peaks observed for
Form A of compound A.
TABLE-US-00006 TABLE 5 FT-Raman peak listing for Form A of compound
A. Raman Shift (cm .sup.-1) 3085 1105 3052 1042 3009 975 2924 895
2902 847 2873 783 2826 742 1578 727 1512 715 1461 703 1447 628 1424
613 1341 564 1327 542 1251 -- 1223 --
Table 6, shown below, sets forth the .sup.13C NMR peaks observed
for Form A of compound A.
TABLE-US-00007 TABLE 6 .sup.13C NMR peak listing for Form A of
compound A. Peak Positions in Parts per Million (ppm) 12.8 15.0
20.4 33.9 60.4 66.7 71.8 75.4 116.6 143.7 149.6 154.2 163.0
Table 7, shown below, sets forth selected .sup.13C NMR peaks and
chemical shifts from downfield peaks observed for Form A of
compound A.
TABLE-US-00008 TABLE 7 .sup.13C NMR peaks and chemical shifts for
Form A of compound A. Peak Positions in Parts .DELTA. (ppm) from
the per Million (ppm) most downfield peak 116.6 46 143.7 19 149.6
13 154.2 9 163.0
FIG. 1 depicts an XRPD pattern of Form A of compound A.
FIG. 2 depicts a DSC trace of Form A of compound A.
FIG. 3 depicts a TGA trace of Form A of compound A.
FIG. 4 depicts a DVS trace of Form A of compound A.
FIG. 5 depicts an XRPD pattern of Form A of compound A before (top)
and after (bottom) DVS analysis.
FIG. 6 depicts an FT-IR spectra of Form A of compound A.
FIG. 7 depicts an FT-Raman spectra of Form A of compound A.
FIG. 8 depicts a solid-state .sup.13C spectra of Form A of compound
A.
FIG. 9 depicts an optical microscope image of Form A of compound
A.
Form A of compound A was observed to have the characteristics
described below.
Based on XRPD data, Form A of compound A is crystalline and shows
sharp and well resolved x-ray diffraction signals.
Based on optical microscopy images, Form A of compound A shows
blade shaped crystals of similar size and shape.
Form A of compound A loses the water of hydration and exhibits a
melting point near 196.degree. C. based on the DSC data.
Form A of compound A is hydrated based on TG and KF data,
containing between 1.2 and 1.4 moles of water per mole of form A of
compound A.
Form A of compound A is stable under various humidity conditions.
It is moderately hygroscopic based on the DVS data where
approximately 9.3% of moisture gain was observed during the
moisture sorption, and about 2% of moisture loss was observed
during the desorption cycle. The crystalline form remained
unchanged after the DVS analysis where the sample was exposed up to
95% RH (relative humidity), and down to 5% RH.
Form A of compound A is stable when milled in the presence of water
or when stirred in water between room temperature and 60.degree.
C.
Form A of compound A is more stable than Form B in solvent systems
having water activity greater or equal to 0.72. If the solvent
system has higher than or equal water activity of 0.72, and the two
crystalline forms are mixed, the mixture converts to Form A. The
solvent systems can be mixture of any organic solvents and organic
solvents containing water.
Form A of compound A has a solid-state .sup.13C NMR spectrum
containing single .sup.13C signals for each carbon position in the
chemical structure. Therefore, there is one molecule in the
asymmetric unit of crystalline form A.
Based on the above, form A of compound A is a moderately
hygroscopic, stable, hydrated, crystalline material.
Example 2--Preparation of Free Base Form B of Compound A
##STR00013## Form B of Compound A
Form B of compound A was prepared as described below.
Form B of Compound A--Preparation Method 1
To a 20 mL glass vial was added 200.4 mg of Form A of Compound A
and 3.0 mL of acetone. A magnetic stir bar was added and the vial
was capped. The vial was placed on a heating/stirring plate set at
60.degree. C. and the slurry was stirred magnetically for 3 days.
The vial was centrifuged for 10 minutes and the mother liquor was
decanted. A dry air purge was directed into the vial for 10 minutes
to dry the solid. The vial was then placed in a room temperature
vacuum desiccator for 2 hours.
Form B of Compound A--Preparation Method 2
To a 1-dram glass vial was added 17.2 mg of Form A of Compound A
and 1 mL of ethyl acetate. The slurry was stirred magnetically on a
heating/stirring plate set to 60.degree. C. and ethanol (absolute)
was added until dissolution occurred (added 1 mL). The stir bar was
removed, the vial capped, and the heat turned off. Once cooled to
ambient temperature, no solid was observed and the vial was left at
ambient temperature overnight, during which time crystallization
did not occur. The vial was then placed in a refrigerator at about
5.degree. C. and left for 3 days, during which time crystallization
did not occur. The vial was then placed in a freezer at about
-15.degree. C. and left for 2 days, during which time
crystallization occurred. The solid was recovered by
filtration.
Form B of Compound A--Preparation Method 3
To a plastic grinding cup was added 18.4 mg of Form A of Compound A
and 10 .mu.L of ethanol. A stainless-steel ball was added. The
sample was then milled on a Retsch mill at 100% power for 20
minutes.
Form B of Compound A--Preparation Method 4
To a 1-gram glass vial was added 3.8 mg of Form A of Compound A and
0.7 mL of tetrahydrofuran. The solid dissolved. The vial was then
placed into a 20 mL glass vial containing 2 mL of hexanes. The 20
mL vial was capped and the sample left at ambient temperature for 6
days, during which crystallization occurred. The solvent was
decanted and the solids allowed to air dry.
Table 2, supra, is reproduced below and sets forth the X-ray
diffraction peaks observed for Form B of compound A.
TABLE-US-00009 TABLE 2 XRPD Peak Positions for Form B of Compound
A. Relative Relative Relative .degree.2.theta. Intensity
.degree.2.theta. Intensity .degree.2.theta. In- tensity 4.7 2.43
20.1 88.35 29.5 4.27 7.6 3.96 21.0 42.70 29.9 3.19 9.5 14.73 21.5
68.69 30.2 6.20 10.0 10.55 23.0 2.13 30.6 7.95 10.5 7.20 23.8 53.95
31.6 4.20 13.8 20.73 24.3 8.09 32.3 1.42 14.2 10.53 24.6 3.80 32.7
5.03 14.7 40.39 25.4 5.74 33.1 4.67 15.2 6.59 25.6 8.51 33.6 3.56
15.4 14.70 25.9 35.31 35.9 7.11 16.2 4.80 26.2 20.76 37.0 2.87 17.1
24.58 26.6 16.53 37.4 1.78 17.9 58.03 27.6 7.29 39.0 1.26 18.3
12.94 28.8 25.11 -- -- 19.0 100 29.1 8.40 -- --
Table 8, shown below, sets forth the FT-IR peaks observed for Form
B of compound A.
TABLE-US-00010 TABLE 8 FT-IR peak listing for Form B of compound A.
Wavenumbers (cm .sup.-1) 3307 1335 835 3248 1298 791 3172 1239 750
3114 1205 721 2898 1190 694 2867 1171 668 1667 1120 639 1589 1093
613 1573 1074 607 1502 1042 574 1443 1023 553 1432 999 499 1409 970
436 1379 932 427 1368 884 418 1347 858 401
Table 9, shown below, sets forth the FT-Raman peaks observed for
Form B of compound A.
TABLE-US-00011 TABLE 9 FT-Raman peak listing for Form B of compound
A. Raman Shift (cm .sup.-1) 3511 997 3424 931 3115 837 3036 788
2931 750 2900 715 2731 669 1570 641 1502 613 1455 546 1371 446 1337
433 1319 446 1288 403 1248 306 1207 183 1190 160 1039 --
Table 10, shown below, sets forth the .sup.13C NMR peaks observed
for Form B of compound A.
TABLE-US-00012 TABLE 10 .sup.13C NMR peak listing for Form B of
compound A. Peak Positions in Parts per Million (ppm) 12.8 23.2
36.0 37.5 61.9 63.8 68.2 73.9 76.4 77.4 116.7 136.3 137.9 150.4
155.3 165.3
Table 11, shown below, sets forth selected .sup.13C NMR peaks and
chemical shifts from downfield peaks observed for Form B of
compound A.
TABLE-US-00013 TABLE 11 .sup.13C NMR peaks and chemical shifts for
Form B of compound A. Peak Positions in Parts .DELTA. (ppm) from
the per Million (ppm) most downfield peak 116.7 49 136.3 29 137.9
27 150.4 15 155.3 10 165.3
FIG. 10 depicts an XRPD pattern of Form B of compound A.
FIG. 11 depicts a DSC trace of Form B of compound A.
FIG. 12 depicts a TGA trace of Form B of compound A.
FIG. 13 depicts a DVS trace of Form B of compound A.
FIG. 14 depicts an XRPD pattern of Form B of compound A before
(top) and after (bottom) DVS analysis.
FIG. 15 depicts an FT-IR spectra of Form B of compound A.
FIG. 16 depicts an FT-Raman spectra of Form B of compound A.
FIG. 17 depicts a solid-state .sup.13C spectra of Form B of
compound A.
FIG. 18 depicts an optical microscope image of Form B of compound
A.
Form B of compound A was observed to have the characteristics
described below.
Based on XRPD data, Form B of compound A is crystalline and shows
sharp and well resolved x-ray diffraction signals.
Based on optical microscopy images, Form B of compound A shows
irregular shaped crystals of similar size and shape.
Form B of compound A exhibits a melting point near 196.degree. C.
based on the DSC data.
Form B of compound A is anhydrous and non-solvated based on TG and
KF data.
Form B of compound A is moderately hygroscopic based on the DVS
data where approximately 6.4% of moisture gain was observed during
the moisture sorption. During the desorption cycle, Form B of
compound A lost all of the moisture gain. Furthermore, the
crystalline form remained unchanged after the DVS analysis where
the sample was exposed up to 95% RH and down to 5% RH.
Form B of compound A is more stable than Form A when slurried in
organic/water solvent systems having water activity less than or
equal to 0.63. The solvent systems can be mixture of any organic
solvents and organic solvents containing water.
Form B of compound A has a solid-state .sup.13C NMR spectrum
containing certain peaks which are clearly doubled. Therefore,
there are two conformationally-different molecules in the
asymmetric unit of crystalline form B.
Based on the above, form B of compound A is a moderately
hygroscopic, stable, unsolvated, anhydrous crystalline
material.
Example 3--Single Crystal Studies of Compound A
##STR00014##
Diffraction data for structural determination of compound A will be
generated by analysis with an electron cryo-microscope (Cryo-TEM)
using the micro-electron-diffraction (microED) technique. MicroED
techniques have been described by Jones et al., ACS Central Science
2018, 4, 1587-1592; Gruene et al., Angew. Chem. Int. Ed. 2018, 57,
16313-16317; and Shi et al., eLife 2013, 2, e01345, doi:
10.7554/eLife.01345.
Materials and Methods
Compound A will be prepared according to Example A described above,
supra, with no additional crystallization or chemical modification
other than crushing, grinding, trituration, milling, or other means
of particle size reduction.
To prepare samples of compound A for microED, approximately 1 mg of
compound A will be placed between two microscope slides and ground
to a fine powder. The ground powder will be placed into an
Eppendorf tube along with a TEM grid and shaken. The loaded TEM
grid will then be removed from the Eppendorf tube and gently tapped
against a filter paper to remove excess powder. Once sample grids
of compound A are prepared, they will be subsequently plunged into
liquid nitrogen, placed into the sample cartridge, and loaded into
the microscope for analysis.
A holey carbon copper grid will be cooled to liquid nitrogen
temperatures and transferred to a cryo electron microscope
operating at an acceleration voltage of 200 kV (Thermo Fisher Talos
Arctica). 140 degrees of diffraction data will be collected from a
single nano crystal by continuous rotation at 0.5 degrees per
second. An entire data set will be collected as a movie using a
bottom mount CetaD CMOS detector fitted with a thick scintillator
for diffraction studies. Software written to convert the movie
frames into SigmaTel Motion Video (SMV) format will allow for
processing in X-ray detector software (XDS).
While we have described a number of embodiments of this invention,
it is apparent that our basic examples may be altered to provide
other embodiments that utilize the compounds and methods of this
invention. Therefore, it will be appreciated that the scope of this
invention is to be defined by the appended claims rather than by
the specific embodiments that have been represented by way of
example.
* * * * *
References